ࡱ> ^ @bjbj00.TRbRb(<<<<d=(h>`BBBBBzfDtD<ceeeeee$(RzEBBEEBBZE:BBcEc6B> EU <4l۬?$lT.X.8((.TEEEEEEE((4 < (( <Botulinum toksina tipa A i kolinergi ni sustav Botulinum toxin type A and cholinergic system Lidija Bach-Rojecky1, Maja Relja2, Boris Filipovi3, Zdravko Lackovi3 1Zavod za farmakologiju Farmaceutsko-biokemijskog fakulteta Sveu iliata u Zagrebu 2Neuroloaka klinika Medicinskog fakulteta Sveu iliata u Zagrebu 3Zavod za farmakologiju & Hrvatski institut za istra~ivanje mozga Medicinskog fakulteta Sveu iliata u Zagrebu Dr. sc. Lidija Bach-Rojecky Zavod za farmakologiju Farmaceutsko-biokemijskog fakulteta Sveu iliata u Zagrebu Prof. dr. sc. Maja Relja Neuroloaka klinika Medicinskog fakulteta Sveu iliata u Zagrebu Boris Filipovi, cand. med. Zavod za farmakologiju & Hrvatski institut za istra~ivanje mozga Medicinskog fakulteta Sveu iliata u Zagrebu Prof. dr. sc. Zdravko Lackovi Zavod za farmakologiju & Hrvatski institut za istra~ivanje mozga Medicinskog fakulteta Sveu iliata u Zagrebu Adresa autora: Zavod za farmakologiju Farmaceutsko-biokemijskog fakulteta Sveu iliata u Zagrebu, Domagojeva 2, 10 000 Zagreb, Hrvatska Adresa za dopisivanje: Prof. dr. sc. Zdravko Lackovi Zavod za farmakologiju & Hrvatski institut za istra~ivanje mozga Medicinskog fakulteta Sveu iliata u Zagrebu, `alata 11, 10 000 Zagreb Skraeni naslov lanka: Botulinum toksin A Sa~etak U anaerobnoj bakteriji Clostridium botulinum nastaje sedam razli itih serotipova botulinum neurotoksina (A-G), koji prije e lu enje acetilkolina iz motori kih i autonomnih kolinergi nih ~ivaca. Najpoznatije i najviae istra~ivano mjesto djelovanja botulinum toksina tipa A (BT-A) je neuromuskularna veza gdje cijepa SNAP-25, jedan od tri klju na proteina pri neuroegzocitozi. Posljedica je dugotrajna paraliza zahvaene neuromuskularne veze. Iako je BT-A jedna od najtoksi nijih tvari u prirodi koja uzrokuje botulizam, posljednjih dvadesetak godina injiciranje nanogramskih koli ina u specifi ne miaie koristi se u terapiji razli itih poremeaja karakteriziranih poveanom miainom kontrakcijom, poput distonija, spasti nosti u dje je paralize i sl., ali i u poremeaja autonomnog ~iv anog sustava, kao ato je hiperhidroza. Dugotrajno djelovanje (nekoliko mjeseci) nakon jednokratne ciljane primjene je osnovno obilje~je terapije s BT-A. Iako se o akutnom mehanizmu djelovanja na neuromuskularnu vezu najviae zna, joa uvijek nije razjaanjeno na koji na in BT-A prolazi kroz epitelne barijere, niti koji je mehanizam specifi nog prepoznavanja perifernih kolinergi nih ~iv anih zavraetaka. Posebno je zna ajno da mehanizam dugotrajnog djelovanja, ato je temelj klini ke uporabe BT-A, za sada nije dovoljno jasan. Klju ne rije i: botulinum toksin, botulizam, kolinergi ni sustav, neuromuskularna veza Summary Botulinum toxin type A and cholinergic system Anaerobic bacteria Clostridium botulinum produces seven different serotypes of botulinum neurotoxins (A-G), which specifically act at the peripheral cholinergic nerve terminals blocking the release of acethylcholine. Primary site of action of botulinum toxin type A (BT-A) is neuromuscular end plate where it specifically cleaves SNAP-25, one of the proteins neccessary for neuroegzocytosis. The cosequence is long-lasting muscle paralysis. Although BT-A is one of the most potent toxins in nature, over the last 20 years, intramuscular injections of nanogram quantities of BT-A has been used to treat various conditions characterized by increased muscle contraction, like dystonias, spasticity related to cerebral palsy etc but also for autonomic nervous system dysorders, like hyperhydrosis. Long duration of action (several months) after peripheral application is the most prominent feature of the toxins action. Although the acute mechanism of action on neuromusular junction is largely investigated, there are still some unknowns related to: the passage of BT-A through epithelial barriers, specific recognition of peripheral cholinergic neurons. The mechanism of long duration of action, which is the base of therapeutic use of BT-A, is poorly understood. Key words: botulinum toxin, botulism, cholinergic system, neuromuscular junction Clostridium botulinum je gram pozitivna sporogena bakterija koja u anaerobnim uvjetima prelazi u vegetativni oblik, te koja stvara sedam razli itih serotipova botulinum toksina, i to tip: A, B, C1 D, E, F i G. Ovi toksini djeluju specifi no na perifernim kolinergi nim ~iv anim zavraecima, gdje prije e egzocitozu acetilkolina. Serotipovi A, B, E i ponekad F uzrokuju botulizam u ljudi, dok su serotipovi C, D i E odgovorni za botulizam u drugih sisavaca, ptica i riba. Razlike u osjetljivosti vrsta na pojedine serotipove nisu do kraja objaanjene.1 Spore bakterije su otporne na visoke temperature, a esto se nalaze u zemlji, vodenim nanosima i ribama. U anaerobnim uvjetima, ako sredina nije previae kisela (manja opasnost zakiseljenih  zimnica i sl.), razviju se vegetativni oblici koji stvaraju botulinum toksin(e), iji je u inak bez lije enja vrlo esto smrtonosan.1 Ovim preglednim radom prikazat emo osnovne osobine djelovanja botulinum toksina tipa A (BT-A) na periferni kolinergi ni sustav. Upravo je taj u inak temelj trovanja, ali i temelj danaanje ciljane terapijske primjene BT-A. Struktura BT-A BT-A se stvara kao kompleks od 900 kDa, a ini ga neurotoksi na - bioloaki aktivna komponenta veli ine 150 kDa i netoksi ni proteini. Netoksi ni proteini nisu fizioloaki aktivni, ve se smatra da atite bioloaki aktivni dio molekule od proteolize i denaturacije pri visokoj temperaturi ili kiselom pH, npr. u probavnom sustavu prilikom peroralnog trovanja toksinom. Bioloaki aktivni dio molekule oblikuju dva lanca povezana disulfidnom vezom, a ini ga 1296 aminokiselina.2 Dugi lanac, veli ine oko 100 kDa, odgovoran je za vezanje neurotoksina za presinapti ke membrane, dok kratki lanac (50 kDa) posjeduje endopeptidaznu aktivnost, te specifi no cijepa klju ne proteine u procesu vezanja sinapti kih mjehuria s membranom.3 Trodimenzionalna struktura pokazuje da se aktivni dio BT-A sastoji od tri domene, svaka veli ine oko 50 kDa. Dugi lanac ine dvije domene, i to jedna  ve~ua domena, odgovorna za vezanje neurotoksina za membranu, dok druga - translokacijska domena omoguuje ulazak toksina u stanicu. Trea domena BT-A je aktivna i posjeduje endopeptidaznu aktivnost (kratki lanac) (Slika 1). 4 Ulazak BT-A u organizam uslijed trovanja Od svih sedam serotipova botulinum toksina, najotrovniji je BT-A, pri emu se procjenjuje da je za ovjeka letalna koli ina kristalini nog toksina oko 70 (g kod peroralnog unoaenja, 0,09-0,15 g uslijed intravenske i intramuskularne primjene, odnosno 0,70-0,90 (g ako se inhalira, ato ga ini najpotentnijim otrovom u prirodi, te predstavlja i prijetnju kao potencijalno bojno oru~je.5 Mehanizam ulaska BT-A u organizam razmjerno je slabo istra~en. Toksin u organizam mo~e ui putem probavnog trakta, udisanjem i putem rana: 1. Premda je rije  o velikoj proteinskoj molekuli, ona se uspijeva apsorbirati iz probavnog trakta. Tako BT-A pripada rijetkim proteinskim molekulama koje odolijevaju uvjetima u ~elucu i crijevima, te se uspijevaju apsorbirati i zadr~ati bioloaku aktivnost/toksi nost. Nedavnim je istra~ivanjem fluorescentnim ozna avanjem molekule toksina i vizualizacijom njegova kretanja kroz probavni sustav pokazano da se toksin ve~e na apikalnoj povraini epitelnih stanica tankog crijeva, nakon ega se internalizira kroz apikalnu membranu (unutar 5 min). Nakon internalizacije, molekule toksina se rasprae po citosolu, te migriraju prema bazolateralnoj membrani epitelnih stanica kroz koju prolaze transcitozom nepromijenjene.6 2. Botulinum toksin mo~e ui u organizam i kroz respiratorni sustav, nakon inhalacije. Kao i u slu aju stanica probavnog sustava, alveolarne epitelne stanice ili stanice nazalnog epitela ve~u i prenose toksin u smjeru bazolateralne membrane gdje on izlazi iz stanica u nepromijenjenom, aktivnom obliku.7 Nakon ulaska u sistemsku cirkulaciju, pretpostavlja se da BT-A izlazi iz krvnih ~ila, difundira kroz izvanstani ni prostor, te kona no dolazi do ciljnih organa, tj. kolinergi nih ~iv anih zavraetaka. Meutim, mehanizam prolaska kroz endotelne barijere joa uvijek nije dovoljno istra~en. Mogue je da se, kao i kod stanica probavnog sustava, radi o endocitozi i transcitozi, a mogu je i paracelularni prolazak. Uvrije~eno je mialjenje da BT-A ne prolazi krvno-mo~danu barijeru budui da su simptomi botulizma uglavnom posljedica periferne blokade kolinergi nih ~ivaca. 3. Botulinum toksin u organizam mo~e ui i putem otvorenih rana ili ranjavanjem one iaenim predmetima (uklju ivo injekcione igle).8 Botulizam Mogue je razlikovati nekoliko klini kih tipova trovanja botulinum toksinima  obi no se spominje 5: klasi ni botulizam nastao trovanjem s hranom (food-borne botulism), infantilni botulizam (infant botulism), skriveni botulizam (hidden botulism), botulizam iz rana (wound botulism), te profesionalni botulizam. Godianje se u SAD-u prijavi oko 200 slu ajeva razli itih oblika botulizma.5 Klasi ni, i naj eai oblik botulizma, nastaje uslijed trovanja hranom kontaminiranom s neurotoksinom, i to naj eae konzerviranom hranom kune proizvodnje (zimnica, kukuruz, aparoge, mrkva, krumpir).5 Infantilni, sve eai oblik botulizma, karakteristi an je za dojen ad (3-9 mjeseci) zbog specijalnih uvjeta probavnog trakta, a naziva se joa i intestinalnim oblikom. Za razliku od klasi nog oblika, rije  je o kombinaciji infekcije i intoksikacije. Iz spora unesenih u organizam putem hrane, u povoljnim uvjetima, razvija se vegetativni oblik bakterije koja in vivo stvara toksin. Smatra se da je ovaj oblik botulizma naj eae uzrokovan konzumiranjem meda. Tako su, na primjer, ispitivanja meda u Kaliforniji i Brazilu pokazala da je ak od 7% do 10 % uzoraka sadr~avalo spore Clostridium botulinum.9,10 Skriveni botulizam je naziv za intestinalni oblik botulizma, ali u odraslih. Uslijed abnormalnih uvjeta u probavnom sustavu, kao ato je aklorhidrija, promjene uslijed kroni ne antibiotske terapije ili operativnih zahvata probavnog sustava i sl., iz unesenih spora se razvija vegetativni oblik bakterije koji stvara toksin.5 Botulizam nastao infekcijom rana je sve eai, posebno zbog sve veeg broja ovisnika o drogama. Ovisnici su zara~eni itavim nizom patogenih organizama, pa tako i s Clostridium botulinum, koja je u supkutanom apscesu izvor botulinum toksina. Prvi je puta ovaj oblik botulizma opisan kod ovisnika osamdesetih godina u SAD-u, da bi danas postao jedan od eaih oblika botulizma u SAD-u, ali i u Velikoj Britaniji, gdje su od po etka 2000. godine do prosinca 2002. godine dijagnosticirana 33 slu aja intoksiciranih ovisnika.8 Profesionalni oblik botulizma mo~e nastati uslijed izlo~enosti toksinu u laboratorijima ili pri njegovoj industrijskoj proizvodnji, pri emu je naj eai put zaraze inhalacija toksina. Blagi oblik botulizma mo~e nastati i kao nuspojava terapijske primjene, a uslijed sistemskog airenja toksina.5 Klini ke manifestacije botulizma su karakteristi ne za sve oblike trovanja, a obi no se javljaju unutar 12-72 sata, osim kod intestinalnog botulizma gdje je vrijeme inkubacije nepoznato. Botulizam je prepoznat kroz trijadu znakova: simetri na paraliza koja kree od kranijalnih miaia, afebrilitet, te o uvanost kognitivnih i senzornih funkcija. Simptomi su posljedica smanjenja u inka motori kih i autonomnih kolinergi nih neurona: zamuenje vida, dvoslike, ptoza, diplopija, suha usta, teakoe gutanja, disfonija, opa slabost, mu nina, konstipacija, inkontinencija, abdominalna bol, opa miaina slabost nakon koje nastupa paraliza, koja se postupno descendentno razvija (prvo ramena, pa ruke itd.). Smrt nastupa zbog nemogunosti disanja koja je posljedica kljenuti diane muskulature (pa spasonosna mo~e biti mehani ka ventilacija).5,11 Botulizam se ponekad pogreano dijagnosticira kao Guillain-Barr sindrom, mijastenija gravis, mo~dani udar, Lambert-Eaton sindrom ili kao intoksikacija depresorima sredianjeg ~iv anog sustava. Za terapiju botulizma najva~nija je brza dijagnoza. Terapija je dugotrajna i sastoji se od intenzivne njege koja mo~e zahtijevati i umjetnu ventilaciju tijekom nekoliko mjeseci, a ako je dijagnoza brzo postavljena klju no mo~e biti davanje antitoksina (protutijela).11 Danas trovanje s botulinum toksinom zavraava smrtno u 5-10 % bolesnika.1 Molekularni mehanizam djelovanja BT-A Mehanizam djelovanja BT-A u presinapti kom neuronu mo~e se opisati u nekoliko koraka (Slika 2).7,12 (1) Prvi je korak vezanje botulinum toksina za akceptore (vezna mjesta), za koje je tradicionalno uvjerenje da postoje primarno na stani nim membranama kolinergi nih neurona. Unato  brojnim istra~ivanjima potencijalnih veznih mjesta na presinapti kim membranama, ona su tek djelomi no identificirana. Predlo~en je model dvostrukog receptora, gdje se pretpostavlja da se ve~ua domena dugog lanca sastoji od dvije pod-domene, od kojih se jedna ve~e za glikoproteine, dok se druga ve~e za poligangliozide u stani noj membrani.12 U slu aju BT-A, in vitro je naeno da se ve~e na protein ozna en kao SV2 koji je sastavni dio sinapti kih vezikula13, ato bi se slagalo s nekim pretpostavkama da je ulazak botulinum toksina u ~iv ane okon ine ovisan o aktivnosti neurona. Naime proteini vezani uz vezikule bi se trebali nai na povraini stanice pri egzocitozi sinapti kog mjehuria. (2) Nakon specifi nog vezanja, slijede procesi internalizacije i translokacije toksina u citosol. Toksin se internalizira procesom endocitoze, ovisno o temperaturi i energiji. Proces translokacije zapo inje promjenama u strukturi toksina pod utjecajem kiselog pH u endosomu, ugradnje toksina u membranu endosoma, translokacije kratkog lanca s luminalne na citosolnu povrainu membrane endosoma, redukcije disulfidne veze, te kona no odvajanja kratkog od dugog lanca. 12 (3) Kratki lanac BT-A je specifi na, o cinku-ovisna endoproteaza koja cijepa SNAP-25 (SyNaptosomal Associated Protein veli ine 25 kDa), jedan od tri klju na proteina u procesu neuroegzocitoze. SNAP-25, sinaptobrevin i sintaksini se zajedni kim imenom zovu SNARE (Soluble N-ethylmaleimid fusion protein Attachement Protein (SNAP) Receptor) proteinima, a omoguuju fuziju membrana sinapti kog mjehuria i presinapti ke membrane neurona.14 Osim BT-A, SNAP-25 cijepaju i BT-C1 i BT-E, serotipovi B, D, F i G cijepaju sinaptobrevin ili VAMP (Vesicule-Associated Membrane Protein), a tip C1 cijepa i sintaksine. BT-A i neuromuskularna veza Zbog navedene nemogunosti egzocitoze i nemogunosti lu enja acetilkolina, neuromuskularna veza postaje paralizirana, te gubi funkcionalnost. Miaina vlakna postepeno atrofiraju, dok se motorna plo a poveava. Istodobno dolazi do stvaranja, tj. klicanja (engl. sprouting) novih ogranaka motoneurona koji sadr~e proteine uklju ene u proces neuroegzocitoze.12,15 Remodeliranje neuromuskularne veze zapo inje klicanjem kratkih ogranaka ve 4 dana nakon intramuskularnog injiciranja BT-A. Ogranci se u sljedea 4 tjedna postepeno poveavaju, prote~ui se paralelno s longitudinalnom osi miainog vlakna, te preuzimaju funkciju egzocitoze acetilkolina. Na postsinapti kim membranama takoer dolazi do reorganizacije nikotinskih receptora koji su sada smjeateni nasuprot novostvorenim funkcionalnim ograncima. Pritom se poveava broj motornih plo a na jednom miainom vlaknu, kao i broj vlakana inerviranih jednim motornim aksonom.15 Postepeno vraanje funkcije neuroegzocitoze glavnom ogranku primijeeno je tek nakon 2 mjeseca od injiciranja BT-A, da bi se potpuno oporavilo nakon sljedeih mjesec ili viae dana. Sinapti ka plasti nost uglavnom ovisi o koli ini sinapti ke aktivnosti na prvotnom,  glavnom motornom ~iv anom zavraetku (onome koji je zbog toksina prestao funkcionirati), pri emu redukcija ili blokiranje egzocitoze u trajanju od barem 3 dana promovira stvaranje ogranaka, dok vraanje normalne situacije, tj. ponovna uspostava egzocitoze na glavnom motoneuronu (oko 3 mjeseca za BT-A, nekoliko tjedana za BT-E) uzrokuje propadanje novonastalih ~iv anih okon ina.15 ini se da je sam proces stvaranja novih ogranaka potaknut paralizom-uzrokovanim promjenama u koli ini intrinzi nih i ekstrinzi nih neurotropnih imbenika, kao ato su IGF I i II (Insulin growth factor) u samom miainom vlaknu.16 Meutim, o mehanizmima i molekularnim medijatorima sinapti ke plasti nosti se joa uvijek premalo zna, a pretpostavlja se da su u regulaciju uklju eni i drugi proteini koji posreduju intercelularne interakcije tijekom formiranja, sazrijevanja i odr~avanja neuromuskularne veze. U svakom slu aju, prestanak funkcije glavne okon ine, te izrastanje novih ogranaka predstavljaju va~an model pri studiranju plasti nosti neuromuskularne veze. BT-A i autonomni ~iv ani sustav BT-A inhibira otpuatanje acetilkolina i iz kolinergi nih ~ivaca u autonomnom ~iv anom sustavu (preganglijski simpati ki i parasimpati ki, te postganglijski parasimpati ki ~iv ani zavraeci).17 Tako mo~e prije iti u inak acetilkolina na egzokrinim ~lijezdama, glatkim miaiima i sr anom miaiu. Razli itim pretklini kim eksperimentima ispitivano je djelovanje BT-A na egzokrine ~lijezde, sfinktere i srce (Tablica 1). Nazalna primjena BT-A u zamor adi uzrokuje privremenu degeneraciju nazalnih ~lijezda18, a smanjuju se i simptomi rinitisa u atakora (nazalna sekrecija, kihanje), te edem i infiltracija upalnim stanicama mukozne nazalne sluznice.19 Injiciranje BT-A u parotidne ~lijezde atakora smanjuje sekreciju iz ~lijezda slinovnica u trajanju od barem 14 dana bez zna ajnijih morfoloakih promjena stanica, a uz smanjenje koncentracije acetilkolinesteraze.20 Nedavnim je ispitivanjem pokazano da injiciranje BT-A u parotidne ~lijezde smanjuje imunoreaktivnost neuronalne duaik-2-oksid (NO) sintetaze, te time i stvaranje NO.21 Injiciranje BT-A u prostatu atakora uzrokuje selektivnu kolinergi nu denervaciju, relaksaciju miaia prostate, te dolazi do njene postepene atrofije.22 Osim toga, novijim istra~ivanjem je pokazano da BT-A mijenja stani nu dinamiku uzrokujui apoptozu, inhibira proliferaciju, te dovodi do smanjenja broja (1 adrenergi nih receptora u prostati atakora.23 Nakon injiciranja u mokrani mjehur atakora, BT-A inhibira lu enje acetilkolina i noradrenalina iz eferentnih ~iv anih zavraetaka donjeg dijela urinarnog trakta, dok nakon injiciranja u uretru, blokira lu enje noradrenalina iz simpati kih ~iv anih zavraetaka.24 Ispitivanje djelovanja BT-A na glatke miaie pokazalo je da injiciranje BT-A u Oddijev sfinkter ~u nog mjehura25 te analni sfinkter svinje26 smanjuje kontrakcije sfinktera. Djelovanje BT-A na sr ani miai ispitivano je nakon injiciranja toksina u srce psa, pri emu su inhibirani negativni kronotropni odgovori srca nakon stimulacije vagusa.27 Sinapti ka plasti nost, tj. fenomen klicanja se kod autonomnih ~ivaca tek istra~uje. Imunofluorescentnom detekcijom GAP-43 (growth-associated protein 43)  neuronalnog indikatora stvaranja ogranaka, pokazano da nakon primjene BT-A dolazi do stvaranja novih periglandularnih ogranaka ~ivaca. Meutim, ini se, na osnovu mjerenja imunoreaktivnosti PGP 9,5 proteina (protein gene product 9,5) koji slu~i kao glavni biljeg regeneracije ~iv ane funkcije, da stvaranje novih ogranaka nije praeno reinervacijom ~lijezde ili da je ona vrlo spora.17 Na osnovu ovakvih nalaza pokuaava se objasniti dugotrajnije (do 18 mjeseci) djelovanje BT-A na znojne ~lijezde od onoga na motornoj plo i (3-6 mjeseci). Klini ka primjena BT-A Nekontrolirano airenje botulinum toksina, kao najja eg otrova u prirodi, uzrokuje paralizu miaia, dijela autonomnih funkcija i smrt, ako se ne lije i. Meutim, pokazalo se da je mogue vrlo male koli ine BT-A injicirati u sasvim odreeni miai ili parasimpati ki inervirani organ i tako postii reverzibilnu, ali razmjerno dugotrajnu denervaciju koja mo~e biti klini ki vrlo korisna. Medicinski pripravci. Od svih sedam serotipova botulinum toksina, za sada se u terapiji koriste dva, i to tip A (Botox, Botox Cosmetic Allergan, SAD; Dysport, Ipsen, UK; Xeomin, Merz, Njema ka), i tip B (Myoblock, Elan Pharmaceuticals, SAD). Potentnost im je izra~ena je u internacionalnim jedinicama (i.j.), pri emu jedna jedinica odgovara koli ini toksina koja nakon intraperitonealne primjene prouzro i smrt 50% miaeva (1 i.j. Botox-a odgovara 0,048 ng BT-A). Izmeu razli itih komercijalnih pripravaka BT-A postoje odreene razlike. Tako jednoj jedinici Botox-a po potentnosti odgovaraju 3-4 jedinice Dysport-a, a za razliku od ova dva komercijalna pripravka koji sadr~e BT-A u obliku kompleksa veli ine 900 kDa, najnoviji pripravak Xeomin sadr~i samo bioloaki aktivni dio BT-A veli ine 150 kDa. Indikacije za primjenu BT-A Povoljno djelovanje BT-A, injiciranog u ekstraokularne miaie u pacijenata sa strabizmom, prvi su opisali Scott i sur. ve sedamdesetih i osamdesetih godina proalog stoljea.28 Pokazalo se da u odreenih tipova strabizma terapija s BT-A zna ajno smanjuje potrebu za kirurakom korekcijom. Djelotvornost i sigurnost terapije s BT-A u pacijenata s blefarospazmom pokazana je placebo-kontroliranim dvostruko-slijepim pokusom iz 1987. godine.29 U inak BT-A nastupio je unutar 5 dana od iniciranja u orbicularis oculi, a trajao je 3-4 mjeseca. Lokalna primjena BT-A pokazala se djelotvornom i sigurnom i u lije enju hemifacijalnog spazma ( periferna distonija ) primarnog, ali i sekundarnog oblika - nastalog zbog kompresije ili iritacije facijalnog ~ivca, a karakteriziranog nevoljnim, unilateralnim, nepravilnim toni kim ili kloni kim kontrakcijama miaia inerviranih facijalnim ~ivcem.30 Terapijska primjena BT-A je za navedene poremeaje odobrena 1989. godine od Ameri ke agencije za hranu i lijekove (FDA - Food and Drug Administration). Tsui i sur. prvi su 1986. godine u kontroliranim uvjetima pokazali djelotvornost primjene BT-A u lije enju cervikalne distonije ili spasti kog tortikolisa, naju estalijeg oblika fokalne distonije.31 Distonija je trei po u estalosti poremeaj pokreta u ovjeka. Zahvaa sve dobne skupine, posebice radno aktivnu populaciju, a bez mogunosti djelotvorne medikamentozne terapije. Primjena BT-A zna ajno je utjecala na kvalitetu ~ivota ovih bolesnika i radnu sposobnost. U jednom od kontroliranih pokusa na bolesnicima s cervikalnom distonijom u inak je postao zna ajan nakon 3-4 tjedna i trajao nakon toga oko 6 tjedana (Slika 3).32 Najvei broj otvorenih, kao i kontroliranih studija ispitivanja djelotvornosti BT-A u cervikalnoj distoniji odnosi se na istra~ivanje ne~eljenih u inaka, kao i ograni enja terapije s toksinom, ali i na ine i mjesta injiciranja, djelotvorne doze, te trajanje u inka. 33,34 Primjena BT-A u lije enju cervikalne distonije odobrena je od FDA 2000. godine. Odabir i identifikacija miaia za primjenu BT-A u lije enju raznih oblika fokalnih distonija najva~niji je preduvjet uspjeanosti terapije. Potrebno je naglasiti da je to simptomatska terapija fokalnih distonija, odnosno nekontrolirane miaine kontrakcije. U prosjeku, injiciranje BT-A u lije enju fokalnih distonija ponavlja se svaka 3-4 mjeseca. Za sada, nije dovoljno jasno da li nastup i trajanje u inka BT-A ovisi o dozi, obliku spasticiteta i sl. BT-A (Botox Cosmetic, Allergan, SAD) odobren je za primjenu u kozmeti ke svrhe 2002. godine, i to samo za smanjenje intenziteta tzv.  frown lines izmeu obrva. Osim toga, danas se primjenjuje i za smanjenje izra~enosti facijalnih bora, te za korekciju asimetrije lica zbog ozljeda frontalnog ili drugih ogranaka facijalnih ~ivaca.35,36 Primjena BT-A odobrena je u viae od 40 zemalja, uklju ujui europske zemlje i Kanadu (u SAD-u nije odobrena) u terapiji spasti nosti kod dje je paralize. U oko 70-82% djece je nakon intramuskularnog injiciranja BT-A primijeena redukcija spasti nosti, smanjena je bolnost, a zna ajno je poveana kvaliteta ~ivota pacijenata.37,38 Uspjeanost terapije s BT-A se ispituje i u drugih oblika fokalnih distonija39,40, te kod spasticiteta u multiple skleroze41, kod pacijenata s esencijalnim tremorom ruku42 i sl.(Tablica 2). Ono ato je u klini koj primjeni BT-A bitno novo jesu pokuaaji koriatenja toksina zbog u inaka na autonomne kolinergi ne ~ivce, ponajprije u razli itih sekretornih poremeaja, kao ato su hiperhidroza dlanova43, stopala44 ili aksila45, hipersalivacija46,47, hiperlakrimacija48 (Tablica 2). U multicentri nom, placebo-kontroliranom pokusu kod 145 ispitanika s primarnom aksilarnom hiperhidrozom, za ato je primjena BT-A i odobrena od FDA 2004. godine, intradermalno iniciranje BT-A (100-200 i.j.) smanjuje sekreciju znoja iz apokrinih aksilarnih znojnih ~lijezda za oko aest puta45. Intradermalna primjena BT-A u ljudi ne mijenja veli inu, niti broj tubula znojnih ~lijezda, tj. ne dovodi do njihove atrofije, za razliku od atrofije miaia do koje dolazi nakon intramuskularnog injiciranja toksina, ali se zna ajno smanjuje lumen tubula.17 Djelovanje mo~e trajati do godinu ili dvije od injiciranja jedne doze BT-A38. Intraparotidno injiciranje BT-A (15-30 i.j.) zna ajno smanjuje hipersalivaciju kod djece s cerebralnom paralizom, te kod parkinsoni ara.46,47 Novija klini ka opa~anja ukazuju na mogue povoljno djelovanje BT-A u rijetkih poremeaja, poput Freyevog sindroma49, facijalne kromhidroze50, ali i kod nazalnih simptoma u pacijenata s rinitisom.51 Neke klini ke studije su pokazale da bi se razli iti gastrointestinalni poremeaji, kao ato su ahalazija52,53 i druga spasti na stanja ezofagusa, kroni ne analne fissure54,55, opstipacija kod spazma rektalnog sfinktera56,57 mogli uspjeano lije iti lokalnim injiciranjem BT-A (Tablica 2). U novije vrijeme sve je viae dokaza o djelotvornosti lokalne terapije s BT-A kod razli itih genitourinarnih poremeaja praenih poveanom spasti noau sfinktera, kao ato su neurogena inkontinencija uzrokovana hiperrefleksijom detrusora58,59,60, benigna hipertrofija prostate61, te vaginizam62. Mehanizam djelovanja toksina u navedenih poremeaja povezan je s privremenom kemodenervacijom perifernih kolinergi nih ~iv anih zavraetaka na neuromuskularnoj vezi ili autonomnom ~iv anom sustavu. Joa uvijek nije jasno da li je ulazak toksina u stanicu uvjetovan njenom aktivnoau, ato bi imalo za posljedicu br~i nastup djelovanja BT-A u klini kim stanjima poveane ~iv ane aktivnosti. Meutim, u ljudi paraliti ko djelovanje BT-A injiciranog izravno u kontrahirani miai nastupa tek nakon nekoliko dana (5-7), dok pri trovanju hranom simptomi botulizma nastupaju naj eae 12 do 72 sata nakon konzumiranja kontaminirane hrane (u nekim slu ajevima mo~e proi i viae dana). Nakon primjene u zdravi miai pokusnih ~ivotinja, BT-A uzrokuje paralizu 12-24 h nakon injiciranja.15 Je li rije  o razlikama izmeu vrsta ili razli itoj brzini nastupa djelovanja na zdravi i bolesni miai za sada je teako objasniti, te je o ita potreba za dodatnim istra~ivanjima. Treba spomenuti da se tijekom posljednjih godina poveava broj nalaza o povoljnom djelovanju BT-A kod razli itih bolnih stanja koja prate spasticitet, kao npr. u distonija63, miofascijalnog spazma64, piriformis sindroma65, boli miaino-koatanog porijekla66, ali i u boli koje nisu praene poveanom miainom kontrakcijom. Tako danas postoje opa~anja da BT-A djeluje u bolesnika s kroni nom tenzijskom glavoboljom67,68,69, migrenom70,71, neuropatskom boli72, te u intersticijskom cistitisu73 (Tablica 2). Meutim, ovi antinociceptivni u inci nisu posredovani kolinergi nim ~ivcima i njihov mehanizam nastanka je u vrlo ranim fazama istra~ivanja74,75,76, pa ih neemo prikazati u ovom preglednom lanku. Trajanje u inka BT-A Klini ke studije su pokazale da, nakon jednokratne primjene, BT-A djeluje dugotrajno (3-6 mjeseci nakon intramuskularnog davanja, a i do 18 mjeseci nakon intradermalne primjene kod hiperhidroze). Mehanizam dugotrajnog djelovanja, kao i razlike u trajanju, ovisno o mjestu primjene i indikaciji, nisu dovoljno jasne. Prema nekim pretklini kim istra~ivanjima, dugotrajno djelovanje BT-A posljedica je razli ite brzine stvaranja novih funkcionalnih SNAP-25 proteina77, meutim, nije lako zamisliti da je brzina stvaranja SNAP-25 ovisna o tome na kojem je mjestu molekula pocijepana. Prema drugima, duljina u inka je posredovana dugotrajnim zadr~avanjem aktivnih proteoliti kih jedinica BT-A u neuronima78, meutim, rije  je o mjesecima. Novija su istra~ivanja pokazala da fragmenti SNAP-25A, nastali cijepanjem 9 aminokiselina s BT-A, ulaze u interakcije s ostalim SNARE proteinima meutim, ta veza nije funkcionalna i ne uzrokuje egzocitozu, ve se oblikuju dugotrajno nefunkcionalni kompleksi koji onemoguuju pristup i preuzimanje funkcije novostvorenim molekulama SNAP-25.79 Meutim, teorijski nedostatak ovakve pretpostavke je u tome ato predmnijeva de novo sintezu intaktnog SNAP-25, ali ne i drugih SNARE proteina (inhibiranih fragmentom SNAP-25), a to je malo vjerojatno. Ukratko, iako postoji viae pretpostavki, joa uvijek nema kona nog objaanjenja du~ine djelovanja BT-A  koja je glavni razlog njegove klini ke primjene. U slu aju BT-E, koji cijepa 26 aminokiselina na SNAP-25 proteinu, nastala molekula SNAP-25E ne stvara komplekse s ostalim SNARE proteinima, ve se uklanja s presinapti ke membrane endocitozom i retrogradnim transportom.79 Time su omoguene interakcije novostvorene molekule SNAP-25 s ostalim SNARE proteinima, te fuzija membrana i uspostava egzocitoze, ato objaanjava kratkotrajno djelovanje BT-E (nekoliko dana) opa~eno u pretklini kim istra~ivanjima. Za sada nije mogue objasniti niti prestanak djelovanja, tj. sudbinu bioloaki aktivnog kratkog lanca BT-A u presinapti koj stanici. Mogunosti, kao ato su transport kratkog lanca du~ aksona ili njegova mogua proteoliza u citosolu ili lizosomima zahtijevaju dodatna istra~ivanja. Sigurnost terapije s BT-A Jedna meta-analiza na 2 309 ispitanika (iz 36 kontroliranih, randomiziranih studija uporabe BT-A u razli itim terapijskim indikacijama, kao ato su distonija, hiperhidroza, glavobolja, cerebralna paraliza i dr.) ukazala je na sigurnost i podnoaljivost terapije s BT-A. Nuspojave blagog do srednje jakog intenziteta bile su zastupljene u oko 25% pacijenata tretiranih s BT-A u odnosu na 15% nuspojava prijavljenih kod kontrolne skupine. Nuspojave su bile kratkotrajne, nesistemske, a naj eae je prijavljena lokalna miaina slabost okolnih miaia, vjerojatno nastala uslijed difuzije toksina s mjesta primjene80. Tako je naj eaa nuspojava primjene BT-A kod blefarospazma i strabizma ptoza o nih kapaka i obrva, dok je disfagija naj eaa kod lije enja tortikolisa. Meutim, postoje zabilje~eni slu ajevi sistemskih nuspojava karakteriziranih simptomima blagog botulizma81, a jedna je studija pokazala utjecaj BT-A na smanjenje sr anog ritma82. Stvaranje antitijela koji neutraliziraju djelovanje BT-A zabilje~eno je u oko 3-10% pacijenata, a naj eae se dogaa u pacijenata injiciranih visokim dozama, kao i kod estih re-iniciranja, i to u intervalima manjim od 3 mjeseca, te uslijed dugotrajne terapije s BT-A83. Zaklju ak BT-A, uzro nik botulizma i jedna od najotrovnijih " $ H J L N p r R T 2 4 : <  @JLRT  L.|~x"#0$ӿhBUh{^CJaJhBUh{^6CJaJh{^6CJaJh{^B*CJaJphhBUCJaJh{^6CJ]aJh#CJ]aJh{^CJ]aJh{^5CJ\aJh#CJaJh{^CJH*aJh{^CJaJ6^L p L ( Z  ( @~J468$da$d8T?!""X')++`4478l>@@ELF`FL$d1$C$Eƀ fa$ $d1$a$$da$0$D$R'T'V'X'((r)t)))))++++,,/ /l/p/00d1h1.3L3Z4^4`44455666H6666꿻˝˝˝|vmvvvm jmh{^CJ h{^CJ h=h{^h#CJaJh{^CJH*aJh{^5CJaJh{^CJaJhBUCJ]aJh{^CJ]aJhBUh{^hBUh{^CJH*aJhBUCJaJhBUhBUCJaJhBUhBUCJH*aJhBUh{^CJaJhBUh#CJaJ*6<7>77777V:X:;;;==f>h>l>@@@FFJFLF`FFFF,GHHHHdIfIjI|IJJKKKKLMMMMMOOOOOODRFRHRRRRSSSTT쫼Ԣh{^6CJaJh&JCJH*aJh-CJaJh{^CJH*aJh{^CJ\aJ h#CJhBUCJaJh{^5CJaJ h{^CJH*h{^CJaJ hBUCJ h{^CJ@`FjIKOHR^VXlccd`k ostv|̅1$I$dEƀ fa$$da$ $d1$a$ $  da$T|U~UZV\V^VVXX4_6_<__`bbbfchclccxddddd,g.ghhhhiiiij^kklllooooooooooqq(q*qfqhqqqnrrrh{^5CJ\aJhCJaJh{^6CJ]aJhOGCJaJh{^CJ\aJ h{^\ h{^CJh&JCJH*aJh{^5CJaJh{^CJH*aJhBUCJaJh{^CJaJ=rrsNsPsdsfsvsxssszttuvvv.w@w2x4xxx y"y<{@{{{PT ̅FJ̈ Ԋ؊ҍ֍HJ:< jah#CJ h#CJH* h#CJ h{^CJH* h{^CJ h{^\hOGCJaJh{^CJH*aJh{^6CJ]aJh#CJaJh{^5CJ\aJh{^5CJaJh{^CJaJ;̅\̚RvXjr$d[$\$a$ $da$$d[$\$a$$da$“T\̚ ( <>dfܟTVprrt֢آޣRԤ&:f~pv04ԺԺԱԩԩԩԩhCCJaJh{^6CJaJh#CJaJh{^CJ\aJh{^CJH*aJh{^CJaJh#h{^h{^5CJaJ h{^CJH* h{^CJ hOGCJBƲȲ~δ.<(*pz6Lnr48JNdh  ":<bh: h{^CJH* hCCJ h{^CJh#CJaJhCCJaJh{^CJaJh{^CJH*aJP:F(8<r(,nrDJz>@|(Ѽѳh{^6CJaJh#CJaJh{^CJH*aJh{^5CJaJh{^5CJ\h{^5CJH*\]h{^5CJ\]h{^h{^CJaJhCCJaJh{^CJaJh{^CJH*aJ84Hxj 4!"#$J$dC$Eƀh-a$ $d1$a$$da$$d[$\$a$$da$4(jpr.0""""$$%%B'(((* ++++b,d,|hCJ\aJh{^0JCJaJh{^0J5CJaJh{^6CJaJh{^CJaJ!h{^0J>*B*CJ\aJphjh{^CJU\aJ h{^CJUh#CJaJh{^5CJH*aJh{^5CJaJh{^CJaJh{^CJ\aJ0 tvari u prirodi, u posljednjih je 20-tak godina postao vrijedno terapijsko sredstvo u stanja karakteriziranih poveanom miainom kontrakcijom. Mehanizam terapijskog, kao i toksi nog djelovanja je isti, tj. inhibicija lu enja acetilkolina na perifernim kolinergi nim ~iv anim zavraecima. Meutim, joa uvijek postoji mnogo bitnih pitanja na koje istra~ivanja nisu uspjela odgovoriti. Neka od njih uklju uju mehanizme ulaska toksina u organizam i prolaska kroz endotelne barijere, identifikaciju veznih mjesta na membranama neurona, zatim prestanak djelovanja toksina, te sudbinu bioloaki aktivnog kratkog lanca u presinapti kom neuronu. Najvea zagonetka je joa uvijek du~ina djelovanja, koja je i najva~niji temelj klini ke primjene BT-A. Literatura 1. Anonimno. Botulism. WHO Fact Sheet No.270:2002. 2. Turton K, Chaddock JA, Acharya KR. Botulinum and tetanus neurotoxins: structure, function and therapeutic utility. Trends Biochem Sci 2002;27:552-8. 3. Dolly O. Synaptic transmission: inhibition of neurotransmitter release by botulinum toxins. Headache 2003;43:S16-S24. 4.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Lacy+DB%22%5BAuthor%5D" \o "Click to search for citations by this author." Lacy DB,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Stevens+RC%22%5BAuthor%5D" \o "Click to search for citations by this author." Stevens RC. Sequence homology and structural analysis of the clostridial neurotoxins. J Mol Biol 1999 Sep 3;291(5):1091-104. 5. Working Group on Civilian Biodefense. Botulinum toxin as a biological weapon. Medical and public health management. JAMA 2001;285:1059-70. 6. Ahsan CR, Hajnoczky G, Muktar M, Maksymowych AB, Simpson LL. Visualtisation of binding and transcytosis of botulinum toxin by human intestinal epithelial cells. J Pharmacol Exp Ther 2005 Dec;315(3):1028-35. 7. Simpson LL. Identification of the major steps in botulinum toxin action. Annu Rev Pharmacol Toxicol 2004;44:167-93. 8. Brett MM, Hallas G, Mpamugo O. Wound botulism in the UK and Ireland. J Med Microbiol 2004;53:555-61. 9. Schocken-Iturrino RP, Carneiro MC, Kato E, Sorbara JO, Rossi OD, Gerbasi LE. Study of the presence of the spores of Clostridium botulinum in honey in Brasil. FEMS Immunol Med Micbobiol 1999 Jul;24:379-82. 10. Chin J, Arnon SS, Midura TF. Food and enviromental aspects of infant botulism in California. Rev Infect Dis 1979 Jul-Aug;1:692-7. 11. Maselli RA, Bakshi N. Botulism. Muscle Nerve 2000;23:1137-44. 12. Schiavo G, Matteoli M, Montecucco C. Neurotoxins affecting neuroexocytosis. Physiol Rev 2000;80:718-38. 13. Dong M, Yeh F, William H i sur. SV2 Is the Protein Receptor for Botulinum Neurotoxin A, Published online March 16 2006; 10.1126 / science. 1123654 (Science Express Reports) 14. Montecucco C, Schiavo G, Pantanp S. SNARE complexes and neuroexocytosis:how many, how close? Trends Biochem Sci 2005;30:367-72. 15.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22de+Paiva+A%22%5BAuthor%5D" \o "Click to search for citations by this author." de Paiva A,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Meunier+FA%22%5BAuthor%5D" \o "Click to search for citations by this author." Meunier FA,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Molgo+J%22%5BAuthor%5D" \o "Click to search for citations by this author." Molgo J,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Aoki+KR%22%5BAuthor%5D" \o "Click to search for citations by this author." Aoki KR,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Dolly+JO%22%5BAuthor%5D" \o "Click to search for citations by this author." Dolly JO Functional repair of motor endplates after botulinum neurotoxin type A poisoning: biphasic switch of synaptic activity between nerve sprouts and their parent terminals. Proc Natl Acad Sci USA 1999 Mar 16;96(6):3200-5. 16. Carroni P, Schneider C, Kiefer MC, Zapf J. Role of muscle insulin-like growth factors in nerve sprouting: suppression of terminal sprouting in paralyzed muscle by IGF-binding protein 4. J Cell Biol 1994 May;125(4):893-902. 17. Swartling C, Naver H, Pihk-Lundin I, Hagforsen E, Vahlquist A. Sweat gland morphology and periglandular innervation in essential palmar hyperhdrosis before and after treatment with intradermal botulinum toxin. J Am Acad Dermatol 2004;51:739-45. 18. Rohrbach S, Olthoff A, Laskawi R, Giefer B, Gotz W. Botulinum toxin type A induces apoptosis in nasalglands of guinea pigs. Ann Otol Rhinol Laryngol 2001;110:1045-50. 19. Wen WD, Yuan E, Hou YP, Song YF. Experimental studies for botulinum toxin type A on allergic rhinitis in the rat Zhonghua Er Bi Yan Hou Ke Za Zhi. 2004 Feb;39(2):97-101 20. Ellies M, Laskawi R, Tormahlen G, Gotz W. The effect of local injection of botulinum toxin A on the parotid gland of the rat:an immunohistochemical and morphometric study. J Oral Maxillofac Surg 2000;58:1251-6. 21. Ellies M, Schutz S, Quondamatteo F, Laskawi R. Immunohistochemical investigations of the influence of botulinum toxin A on the immunoreactivity of nNOS in the parotid gland of the rat. J Oral Maxillofac Surg. 2006 Mar;64(3):397-401. 22. Doggweiler R, Zermann D-H, Ishigooka M, Schmidt RA. Botox-induced prostatic involution. The Prostate 1998;37:44-50. 23. Chuang YC, Huang CC, Kang HY i sur. Novel action of botulinum toxin on the stromal and epithelial components of the prostate gland. J Urol. 2006 Mar;175(3 Pt 1):1158-63. 24. Smith CP, Franks ME, McNeil BK i sur. Effect of botulinum toxin A on the autonomic nervous system of the rat lower urinary tract. J Urol 2003;169:1896-900. 25. Sand J, Nordback P, Arvola P, Porsti I, Kalloo A, Pasricha P. Effect of botulinum toxin A on the sphincter of Oddi: an in vivo and in vitro study. Gut 1998;42:507-10. 26.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Jones+OM%22%5BAuthor%5D" \o "Click to search for citations by this author." Jones OM,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Moore+JA%22%5BAuthor%5D" \o "Click to search for citations by this author." Moore JA,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Brading+AF%22%5BAuthor%5D" \o "Click to search for citations by this author." Brading AF,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Mortensen+NJ%22%5BAuthor%5D" \o "Click to search for citations by this author." Mortensen NJ. Botulinum toxin injection inhibits myogenic tone and sympathetic nerve function in the porcine internal anal sphincter.  HYPERLINK "javascript:AL_get(this,%20'jour',%20'Colorectal%20Dis.');" Colorectal Dis 2003 Nov;5(6):552-7. 27. Tsuboi M, Furukawa Y, Kurogouchi F, Nakajima K, Hirose M, Chiba S. Botulinum neurotoxin A blocks cholinergic neurotransmission in the dogf heart. Jpn J Pharmacol 2002;89:249-54. 28. Scott AB. Botulinum toxin injection of eye muscles to correct strabismus.Trans Am Ophthalmol Soc. 1981;79:734-70 29.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=3561773&query_hl=12" Jankovic J, Orman J. Botulinum A toxin for cranial-cervical dystonia: a double-blind, placebo-controlled study. Neurology 1987 Apr;37(4):616-23. 30. Wang A, Jankovic J. Hemifacial spasm: clinical correlates and treatments. Muscle Nerve 1998;21:1740 7. 31. Tsui J, Elisen A, Stossel A, Calne D. Double-blind study of botulinum toxin in spasmodic torticollis. Lancet 1986;2:245-7. 32. Relja M, Klepac N. Botulinum Toxin Type A Improves Life Quality and Rehabilitation in Painful Cervical Dystonia. U: Battistin L, Dam M, Tonin P, ur. Proceedings of the 3rd World Congress in Neurological Rehabilitation. Venice; 2002, str. 111-4. 33. Jankovic J. Treatment of cervical dystonia with botulinum toxin. Mov Disord 2004;19:S109-S115. 34.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Costa+J%22%5BAuthor%5D" \o "Click to search for citations by this author." Costa J,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Espirito%2DSanto+C%22%5BAuthor%5D" \o "Click to search for citations by this author." Espirito-Santo C,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Borges+A%22%5BAuthor%5D" \o "Click to search for citations by this author." Borges A i sur. Botulinum toxin type A therapy for cervical dystonia. Cochrane Database Syst Rev 2005 Jan25;1:CD003633. 35. Carruthers A,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Carruthers+J%22%5BAuthor%5D" \o "Click to search for citations by this author." Carruthers J. Botulinum toxin type A for the treatment of glabellar rhytides. Dermatol Clin 2004 Apr;22(2):137-44. 36.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10517680&query_hl=40" Benedetto AV. The cosmetic uses of botulinum toxin type A. Int J Dermatol 1999 Sep;38:641-55. 37. Koman LA, Paterson Smith B, Balkrishnan R. Spasticity associated with cerebral palsy in children: guidelines for the use of botulinum A toxin. Pediatr Drugs 2003;5:11-23. 38.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Wasiak+J%22%5BAuthor%5D" \o "Click to search for citations by this author." Wasiak J,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Hoare+B%22%5BAuthor%5D" \o "Click to search for citations by this author." Hoare B,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Wallen+M%22%5BAuthor%5D" \o "Click to search for citations by this author." Wallen M.Botulinum toxin A as an adjunct to treatment in the management of the upper limb in children with spastic cerebral palsy. Cochrane Database Syst Rev 2004;4:CD003469. 39. Courey MS, Garrett CG, Billante CR i sur. Outcomes assessment following treatment of spasmodic dysphonia with botulinum toxin. Ann Otol Rhinol Laryngol 2000;109:819 22. 40. Djebbari R, du Montcel S-T, Sangla S, Vidal JS, Gallouedec G, Vidailhet M. Factors predicting improvement in motor disability in writer's cramp treated with botulinum toxin. J Neurol Neurosurg Psychiatry2004;75:688-91. 41.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Lamotte+D%22%5BAuthor%5D" \o "Click to search for citations by this author." Lamotte D,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Thoumie+P%22%5BAuthor%5D" \o "Click to search for citations by this author." Thoumie P. Multiple sclerosis and botulinum toxin. Ann Readapt Med Phys 2003;46:299-302. 42. Brin MF, Lyons KE, Doucette J i sur.. A randomized, double masked, controlled trial of botulinum toxin type A in essential hand tremor. Neurology 2001;56:1523 8. 43. Saadia D, Voustianiouk A, Wang AK, i sur. Botulinum toxin type A in primary palmar hyperhidrosis. Randomized, single-blind, two-dose study. Neurology 2001;57:2095 9. 44.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Naumann+M%22%5BAuthor%5D" \o "Click to search for citations by this author." Naumann M,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Jost+W%22%5BAuthor%5D" \o "Click to search for citations by this author." Jost W. Botulinum toxin treatment of secretory disorders. Mov Disord 2004 Mar;19Supp l 8:137-41. 45. Naumann MK, Lowe NJ. Effect of botulinum toxin type A on quality of life measures in patients with excessive axillary sweating: a randomized controlled trial. Br J Dermatol 2002;147:1218 26. 46. Bothwell JE, Clarke K, Dooley JM i sur. Botulinum toxin A as a tretament for excessive drooling in children. Pediatr Neurol 2002;27:18-22. 47. Pal PK, Calne DB, Calne S i sur. Botulinum toxin A as a treatment for drooling saliva in PD. Neurology 2000;89:1659-63. 48. Keegan DJ, Geerling G, Lee JP, Blake G, Collin JR, Plant GT. Botulinum toxin treatment for hyperlacrimation secondary to aberrant regenerated seventh nerve palsy or salivary gland transplantation.  HYPERLINK "javascript:AL_get(this,%20'jour',%20'Br%20J%20Ophthalmol.');" Br J Ophthalmol. 2002 Jan;86(1):43-6. 49. Arad-Cohen, Blitzer A. Botulinum toxin treatment for symptomatic Frey's syndome. Otolaryngol Head Neck Surg 2000 Feb;122:237-40. 50. Matarasso SL. Treatment of facial chromhidrosis with botulinum toxin type A. J Am Acad Dermatol 2005;52:89-91. 51.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14710908&query_hl=12" Unal M, Sevim S, Dogu O, Vayisoglu Y, Kanik A. Effect of botulinum toxin type A on nasal symptoms in patients with allergic rhinitis: a double-blind, placebo-controlled clinical trial. Acta Otolaryngol 2003 Dec;123(9):1060-3. 52. Schiano TD, Parkman HP, Miller LS i sur. Use of botulinum toxin in the treatment of achalasia. Dig Dis 1998;16:14 22. 53.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Martinek+J%22%5BAuthor%5D" \o "Click to search for citations by this author." Martinek J,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Siroky+M%22%5BAuthor%5D" \o "Click to search for citations by this author." Siroky M,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Plottova+Z%22%5BAuthor%5D" \o "Click to search for citations by this author." Plottova Z,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Bures+J%22%5BAuthor%5D" \o "Click to search for citations by this author." Bures J,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Hep+A%22%5BAuthor%5D" \o "Click to search for citations by this author." Hep A,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Spicak+J%22%5BAuthor%5D" \o "Click to search for citations by this author." Spicak J. Treatment of patients with achalasia with botulinum toxin: a multicenter prospective cohort study. Dis Esophagus 2003;16(3):204-9. 54.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15820455&query_hl=13" Arroyo A, Perez F, Serrano P, Candela F, Lacueva J, Calpena R. Surgical versus chemical (botulinum toxin) sphincterotomy for chronic anal fissure: long-term results of a prospective randomized clinical and manometric study. Am J Surg 2005;189:429-34. 55.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Thornton+MJ%22%5BAuthor%5D" \o "Click to search for citations by this author." Thornton MJ,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Kennedy+ML%22%5BAuthor%5D" \o "Click to search for citations by this author." Kennedy ML,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22King+DW%22%5BAuthor%5D" \o "Click to search for citations by this author." King DW. Prospective manometric assessment of botulinum toxin and its correlation with healing of chronic anal fissure. Dis Colon Rectum 2005 Jul;48(7):1424-31. 56.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11742168&query_hl=47" Ron Y, Avni Y, Lukovetski A i sur. Botulinum toxin type-A in therapy of patients with anismus. Dis Colon Rectum 2001 Dec;44(12):1821-6. 57. Albanese A, Maria G, Bentivoglio A i sur. Severe constipation in Parkinson s disease relieved by botulinum toxin. Mov Disord 1997;12:764 6. 58. Jost WH, Naumann M. Botulinum toxin in neuro-urological disorders. Mov Disord 2004;19Supp 18:142-5. 59.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15947626&query_hl=22" Schurch B, de Seze M, Denys P i sur. Botox Detrusor Hyperreflexia Study Team. Botulinum toxin type A is a safe and effective treatment for neurogenic urinary incontinence: results of a single treatment, randomized, placebo controlled 6-month study. J Urol 2005;174:196-200. 60.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Grosse+J%22%5BAuthor%5D" \o "Click to search for citations by this author." Grosse J,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Kramer+G%22%5BAuthor%5D" \o "Click to search for citations by this author." Kramer G,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Stohrer+M%22%5BAuthor%5D" \o "Click to search for citations by this author." Stohrer M. Success of repeat detrusor injections of botulinum a toxin in patients with severe neurogenic detrusor overactivity and incontinence. Eur Urol 2005;47:653-9. 61. Chuang YC, Chiang PH,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Huang+CC%22%5BAuthor%5D" \o "Click to search for citations by this author." Huang CC,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Yoshimura+N%22%5BAuthor%5D" \o "Click to search for citations by this author." Yoshimura N,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Chancellor+MB%22%5BAuthor%5D" \o "Click to search for citations by this author." Chancellor MB. Botulinum toxin type A improves benign prostatic hyperplasia symptoms in patients with small prostates.  HYPERLINK "javascript:AL_get(this,%20'jour',%20'Urology.');" Urology 2005 Oct;66(4):775-9. 62.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Ghazizadeh+S%22%5BAuthor%5D" \o "Click to search for citations by this author." Ghazizadeh S,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Nikzad+M%22%5BAuthor%5D" \o "Click to search for citations by this author." Nikzad M. Botulinum toxin in the treatment of refractory vaginismus. Obstet Gynecol 2004 Nov;104(5):922-5. 63.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=2300249&query_hl=15" Jankovic J, Schwartz K. Botulinum toxin injections for cervical dystonia. Neurology 1990 Feb;40(2):277-80. 64.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Lang+AM%22%5BAuthor%5D" \o "Click to search for citations by this author." Lang AM. A preliminary comparison of the efficacy and tolerability of botulinum toxin serotypes A and B in the treatment of myofascial pain syndrome: a retrospective, open-label chart review. Clin Ther 2003 Aug;25(8):2268-78. 65.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Childers+MK%22%5BAuthor%5D" \o "Click to search for citations by this author." Childers MK,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Wilson+DJ%22%5BAuthor%5D" \o "Click to search for citations by this author." Wilson DJ,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Gnatz+SM%22%5BAuthor%5D" \o "Click to search for citations by this author." Gnatz SM,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Conway+RR%22%5BAuthor%5D" \o "Click to search for citations by this author." Conway RR,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Sherman+AK%22%5BAuthor%5D" \o "Click to search for citations by this author." Sherman AK Botulinum toxin type A use in piriformis muscle syndrome: a pilot study. Am J Phys Med Rehabil 2002 Oct;81(10):751-9. 66. Foster L, Clapp L, Erickson M, Jabbari B. Botulinum toxin A and chronic low back pain: a randomized double blind study. Neurology 2001;56:1290 3. 67. Relja M. Treatment of tension-type headache by local injection of botulinum toxin. Eur J Neurol 1997;4:S71-S73. 68. Rollnik J D, Tannerberger O, Schubert M, Schneider U, Dangler R. Treatment of tension-type headache with botulinum toxin type A: double-blinded placebo-controlled study. Headache 2000;40:300-5. 69. Relja M, Telarovic S. Botulinum toxin in tension-type headache. J Neurol 2004;25:I/12-I/14. 70. Binder WJ,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Brin+MF%22%5BAuthor%5D" \o "Click to search for citations by this author." Brin MF,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Blitzer+A%22%5BAuthor%5D" \o "Click to search for citations by this author." Blitzer A,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Schoenrock+LD%22%5BAuthor%5D" \o "Click to search for citations by this author." Schoenrock LD,  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Pogoda+JM%22%5BAuthor%5D" \o "Click to search for citations by this author." Pogoda JM.Botulinum toxin type A (BOTOX) for treatment of migraine headaches: an open-label study. Otolaryngol Head Neck Surg 2000 Dec;123(6):669-76. 712.  HYPERLINK "http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15377314&query_hl=11" Evers S, Vollmer-Haase J, Schwaag S, Rahmann A, Husstedt IW, Frese A. Botulinum toxin A in the prophylactic treatment of migraine-a randomized, double-blind, placebo-controlled study. Cephalalgia 2004 Oct;24(10):838-43. 72. Klein AW. The therapeutic potential of botulinum toxin. Dermatol Surg 2004;30:452-5. 73. Smith CP, Radziszewski P, Borkowski A, Somogyi GT, Boone TB, Chancellor MB. Botulinum toxin a has antinociceptive effects in treating interstitial cystitis. Urology 2004;64:871-5. 74. Bach-Rojecky L, Relja M, Lackovic Z. Botulinum toxin type A in experimental neuropathic pain. J Neural Transm 2005;112:215-9. 75. Bach-Rojecky, Lackovic Z. Antinociceptive effect of botulinum toxin type A in rat model of the carrageenan and capsaicin induced pain. Croat Med J 2005;46:55-62. 76. Cui M, Khanijou S, Rubino J, Aoki KR. Subcutaneous administration of botulinum toxin A reduces formalin-induced pain. Pain 2004 Jan;107(1-2):125-33. 77. Eleopra R, Tugnoli V, Rossetto O, De Grandis D, Montecucco C. Different time courses of recovery after poisoning with botulinum neurotoxin serotypeas A and E in humans. Neurosci Lett 1998;256:135-8. 78. Foran PG, Mohammed N, Lisk GO i sur. Evaluation of the therapeutic usefulness of botulinum neurotoxin B, C1, E and F compared with the long lasting type A. J Biol Chem 2003;278:1363-71. 79. Meunier FA, Lisk G, Sesardic D, Dolly JO. Dynamics of motor nerve terminal remodeling unveiled using SNARE-cleaving botulinum toxins: the extent and duration are directed by the sites of the SNAP-25 truncation. Mol Cell Neurosci 2003;22:454-66. 80. Naumann M; Jankovic J. Safety of botulinum toxin type A: a systematic review and meta-analysis.  HYPERLINK "http://www.ingentaconnect.com/content/libra/cmro;jsessionid=qai1ez9umxpo.henrietta" \o "Current Medical Research and Opinion" Curr Med Res Opin 2004;20:981-90. 81. Bhatia KP, Mnchau A, Thompson PD, i sur. Generalised muscular weakness after botulinum toxin injections for dystonia: a report of three cases. J Neurol Neurosurg Psychiatry 1999;67:90-3. 82. Meichsner M, Reichel G. Effect of botulinum toxin A and B on vegetative cardiac innervation. Fortschr Neurol Psychiatr 2005;73(7):409-14. 83. Borodic G, Johnson E, Goodnough M, et al. Botulinum toxin therapy, immunologic resistance, and problems with available materials. Neurology 1996;46:26 9. Slika 1. Shematski prikaz strukture botulinum toksina tipa A Figure 1. Shematic structure of botulinum toxin type A Slika 2. Pretpostavljeni mehanizam djelovanja botulinum toksina tipa A Figure 2. Proposed mechanism of action of botulinum toxin type A Slika 3. Postotak smanjenja te~ine simptoma mjereno kvantitativnom skalom od strane samih bolesnika (tzv. Patient Global Assesement Scale  GAP). *p<0,05 (modificirano prema Relja i Klepac 200232) Figure 3. Percentage of symptoms decrease measured by the Patients Global Assesment Scale (GAS). *p<0.05 (modified according to Relja and Klepac 200232) Tablica 1. Pretklini ka ispitivanja utjecaja botulinum toksina tipa A na autonomni ~iv ani sustav Table 1. Preclinical investigations of botulinum toxin type A influence on autonomic nervous system Pokus ExperimentRezultat Results- Nazalna primjena u atakora Nasal application in rats- privremena degeneracija nazalnih ~lijezda i difuzna;18 smanjenje simptoma alergijskog rinitisa u atakora19 - temporal degeneration of nasal glands and difuse reversibile apoptosis; BT-A reduces symptoms of allergic rhinitis in rats - Injiciranje u parotidnu ~lijezdu atakora Injection in parotid gland in rats- smanjenje kolinergi ke parasimpati ke inervacije i sekrecije tekuine iz ~lijezda slinovnica u trajanju od barem 14 dana bez zna ajnijih morfoloakih promjena stanica20; smanjenje stvaranja duaik oksida21 reduction of cholinergic parasympathetic inervation and secretion of saliva during 14 days without morphological cell changes; inhibition of NO synthesis - Injiciranje toksina u prostatu atakora Botulinum toxin type A injection into rat s prostate- selektivna kolinergi ka denervacija, relaksacija miaia te postepena atrofija prostate22; inhibicija proliferacije, apoptoza, smanjenje broja (1 receptora u prostati atakora23 selective cholinergic denervation, muscle relaxation and prostate atrophy; inhibition of cell proliferation, apoptosis and reduction of (1 receptors in rat's prostate- Injiciranje u mokrani mjehur i uretru atakora Injection into the bladder and urethra of rats- inhibicija lu enja acetilkolina i noradrenalina iz eferentnih ~iv anih zavraetaka donjeg dijela urinarnog trakta u trajanju 30 dana; inhibicija otpuatanje noradrenalina iz stimuliranih simpati kih ~iv anih zavraetaka uretre24; inhibition of egzocytosis of acetylcholine and noradrenaline from efferent parasympathetic nerve endings of lower urinary tract during 30 days; inhibition of noradrenaline secretion from sympaphetic nerve endings of urethra- Injiciranje u Oddijev sfinkter svinje Injection into the pig sphincter of Oddi - inhibirane su kontrakcije sfinktera uslijed djelovanja na kolinergi ke ~iv ane zavraetke25; inhibition of sphincter contractions upon effect on cholinergic nerve endings- Injiciranje u analni sfinkter svinje Injection into the pig anal sphincter- smanjenje kontrakcija analnog sfinktera uslijed djelovanja BT-A na lu enje noradrenalina na ~iv ano- miainoj spojnici26; reduction of anal sphincter contractions due to inhibition of noradrenaline egzocytosis in neuromuscular junction- Injiciranje u srce psa Injection into the sinoatrial fat-pad in dog- inhibirani su negativni kronotropni odgovori srca nakon stimulacije vagusa27; inhibition of negative kronotropic heart responses upon vagus stimulation Tablica 2. Klini ka primjena BT-A (odobrena i u fazi ispitivanja) te tip neurona odgovoran za djelovanje Table 2. Clinical use of BT-A (approved and off-labbel) and type of neuron associated with the effect Odobrena ApprovedTipneurona Type of neuron- Strabizam28 Strabismus- Motoneuroni Motoneurons- Fokalne distonije: Focal dystonias- Blefarospazam29 Blepharospasm - Cervikalna distonija31,32,33,34 Cervical dystonia- Motoneuroni Motoneurons- Hemifacijalni spazam30 Hemifascial spasm- Motoneuroni Motoneurons- Kozmeti ka primjena-bore35,36 Cosmetics-facial lines- Motoneuroni Motoneurons- Dje ja cerebralna paraliza37,38 Cerebral palsy in children- Motoneuroni Motoneurons- Autonomni poremeaji Autonomic dysorders- Primarna aksilarna hiperhidroza43,45 Primary axillary hyperhydrosis - Autonomni AutonomicNeodobrena Off-label- Ostale fokalne distonije Other focal dystonias- Laringealna39 Laryngeal - Profesionalne40 Proffesional- Motoneuroni Motoneurons- Esencijalni tremor ruku42 Essential tremor of hands- Motoneuroni Motoneurons- Spasti nost: Spasticity - Multipla skleroza41 Multiple sclerosis - Motoneuroni Motoneurons- Autonomni poremeaji: Autonomic dysorders- Fokalna hiperhidroza44 Focal hyperhidrosys - Hipersalivacija46,47 Hypersalivation - Hiperlakrimacija48 Hyperlacrimation - Freyev sindrom49 Frey s syndrom- Autonomni Autonomic- Gastrointestinalni poremeaji: Gastrointestinal system dysorders- Ahalazija52,53 Achalasia - Analne fissure54,55 Anal fissure - Spazam rektalnog sfinktera56,57 Anismus - Autonomni Autonomic- Uroloaki poremeaji: Urological dysorders- Neurogena hipereaktivnost mjehura i inkotinencija59,60 Neurogenic bladder hyperactrivity and incotinence - Benigna hiperplazija prostate61 Benign prostate hyperplasia - Vaginizam62 Vaginismus- Autonomni Autonomic- Bolna stanja: Pain conditions- Bol u distonija63 Painfull dystonias - Miofascijalna bol64 Myofascial pain - Piriformis sindrom65 Pyriformis syndrom - Kroni na bol donjeg dijela lea66 Chronic low back pain - Tenziona glavobolja67,68,69 Tension headache- Motoneuroni Motoneurons - Senzorni? Sensory neurons? - Migrena70,71 Migraine - Neuropatska bol72 Neuropathic pain - Intersticijski cistitis73 Interstitial cystitis- Senzorni? Sensory?  Slika 1. Slika 2.   EMBED Excel.Chart.8 \s  $8&D''(*+3x5j78:;=>?2ABI`KLLxNNOLP>RS$d[$\$a$d$da$ $d1$a$d,x,z,~,,------,/.//B/D/0000001111x58 99$:>>????BBCCCCCC8E:EJELEPEREFFFFFFH H"H$H(HIϼϠϠϠϠϠϠϠϠjh{^CJUaJh{^0J56 h{^56h{^0J56h{^0JCJaJh{^CJaJh{^CJ\aJjh{^CJU\aJ!h{^0J>*B*CJ\aJph?IIIIIII`KzK|KKHLJLLLTLVLRMTM|M~MO,OLOTOVOTPR R*B*CJaJphh{^5CJaJjh{^5CJUaJh{^5CJ\aJ h{^6 h{^0J6 h{^56 h{^0J6h{^0J56h{^0J>*B*CJaJphjh{^CJUaJh{^CJaJ!TTbTdThTjTUUUUUU4W6WFWHWXWW(X.X0XLXNXYYYYZZZ[[[[V\t]]]]^^____Z`\`j`l`p`r`aa÷÷˘˘ˏ˘˘˘˘˘h{^0J56CJ\h{^5CJ\jh{^5CJU\aJh{^0J>*B*CJaJphjh{^CJUaJh{^CJaJh{^5CJ\aJh{^5CJaJjh{^5CJUaJ$h{^0J5>*B*CJ\aJph3S(XZN\]cvd6fijBlo>q\rTsvwJ$dC$Eƀq-a$$da$$d[$\$a$$d[$\$a$aaacc6chctcvc"dRd^dddee>f@fgggggghhiiiTiiiiiiiijjjjjk:k*B*CJ\aJphjh{^CJUaJh{^0J5CJaJh{^6CJ]aJh{^CJ]aJh{^CJaJh{^CJ\aJh{^5CJaJh{^5CJ\aJjh{^5CJU\aJ$h{^0J5>*B*CJ\aJph-Hkl l,l0lJlLlmmmmmmnnoooopq$q*qqZs\snsrssssssssssssttt~uuuuuuvwwxxڧjh{^5CJUaJ h{^CJh{^0J>*B*CJaJphh{^5CJaJh{^6CJaJ!h{^0J>*B*CJ\aJphjh{^CJUaJh{^CJ\aJh{^CJ]aJh{^CJaJ5x$y&yT{d{{{{||||||:~<~L~N~R~T~XZdfjlăƃʃ؄ڄ؅څVXڇ܇(*@BFĸĸĸĸĸĸĸĸĸĸĸĸĞĸĸĸĸh{^0J>*B*CJaJphh{^CJ\aJ!h{^0J>*B*CJ\aJphjh{^CJUaJh{^CJaJh{^5CJ]aJh{^5CJaJjh{^5CJUaJ!h{^0J5>*B*CJaJph8wz{Є҇:VxJzJܾP$da$$d[$\$a$$da$$d[$\$a$FH 8:BDBDVrBVbfRTRTʕ̕ܕޕ*,<>BDh{^CJ]aJh{^6CJ]aJh{^0J>*B*CJaJphh{^CJ\aJ!h{^0J>*B*CJ\aJphh{^CJaJjh{^CJUaJD46:<Ԟ֞؞(*8:pr¡ڡܡ(*:<@   :<24BDHڲuh{^5CJ\aJ$h{^0J5>*B*CJ\aJph!h{^0J5>*B*CJaJphjh{^5CJUaJh{^5CJaJh{^0J>*B*CJaJph h{^CJh{^CJ\aJh{^CJaJ!h{^0J>*B*CJ\aJphjh{^CJUaJ.PRhjnp̫Ϋҫԫ,.24|~RdhjĶƶ"$(*z| " "!h{^0J5>*B*CJaJphh{^5CJ\aJh{^5B*CJaJph$h{^0J5>*B*CJ\aJphjh{^5CJUaJh{^5CJaJCPBD$RThj$68&J¹䫚·~·~~ypdh{^56CJ]aJh{^5CJaJ h{^6h{^6CJ] h{^6CJh{^CJOJQJ^J!h{^0J5>*B*CJaJphjh{^5CJUaJh{^CJ\aJh{^5CJ\]aJ h{^CJh{^5CJaJ h{^5CJh{^5CJaJh{^CJaJh{^5CJ\aJ$P0L$d XX]X^X$da$$da$$d[$\$a$ "8TNPRVX0 ,vznrtvdh.02翳󳢔vvvvvvvkvk jah{^CJaJh{^CJH*aJh{^6CJaJh{^CJaJh{^h{^56CJH*]aJ hh1hh156CJH*]aJh{^56CJ]aJh{^5CJaJh{^56CJH*]aJ hh1hh156CJH*]aJh{^56CJ]aJhh156CJ]aJ($V ,.hjf]] d$Ifykd$$Ifl0 # 4 t044 la $d$Ifa$d$d[$\$a$ j|vxz }ykd$$Ifl0 # 4 t044 la d$If HJl}}}}} d$Ifykd$$Ifl0 # 4 t044 laln2}}}}wk $d$Ifa$$If d$Ifykdq$$Ifl0 # 4 t044 la2"Z^|8L":>"NdDN blndh>B26(,$.jtVZ h{^H*h{^h{^5CJaJh{^6CJaJh{^6CJ]aJh{^CJH*aJh{^CJaJ h{^H*\ h{^\Jj&}}}} d$IfykdF$$Ifl0 # 4 t044 lajbN}}}}} d$Ifykd$$Ifl0 # 4 t044 laNP }}}}} d$Ifykd$$Ifl0 # 4 t044 la "$"uumd d$If$If $d$Ifa$dykd$$Ifl0 # 4 t044 la"$@Vrxlxl $d$Ifa$ d$If~kd$$Ifl40L $p t0D%44 laf4"fxxl\lllld$If[$\$ $d$Ifa$ d$If~kdb$$Ifl40L $p t0D%44 laf4 "$@\neeYYY $d$Ifa$ d$Ifkd8$$Ifl4FL@ $ `p t0D%    44 laf4\^ neeYYY $d$Ifa$ d$IfkdS $$Ifl4FL@ $  p t0D%    44 laf4  PneeYYY $d$Ifa$ d$Ifkdn $$Ifl4FL@ $ `p t0D%    44 laf4 nnee_YYee$If$If d$Ifkd $$Ifl4FL@ $  p t0D%    44 laf4qcWI$d$Ifa$ $d$Ifa$$dx$Ifa$kd $$IflFL@ $ p t0D%    44 laHNz0xxxlllllll $d$Ifa$ d$If~kd $$Ifl40L $p t0D%44 laf4 02jqhh\\\ $d$Ifa$ d$Ifkd$$IflFL $\ xp t0D%    44 laDnpqhhhhhh\ $d$Ifa$ d$Ifkd$$IflbFL $\ xp t0D%    44 la8f.Phqhhhhhhhhhhh d$Ifkd$$IflFL $\ xp t0D%    44 la h0Jv"hkd$$IflFL $\ xp t0D%    44 la d$If "$RZ*Bqhhhhhhhhhh d$Ifkd$$IflFL $\ xp t0D%    44 la BDd.\>qhhhhhhhhhhh d$Ifkd$$IflFL $\ xp t0D%    44 la ,>8<>68>rtֽjۋh&JU%jgI h&JCJUVaJmH sH jh&JUh&Jjh{^Ujh{^U h{^H*h{^h{^5CJaJh{^CJH*\aJh{^CJaJh{^CJH*aJ>fekd$$Ifl4FL $`\ xp t0D%    44 laf4 d$If >d_Mii-DM ]i^ikd$$Ifl4FL $ \ xp t0D%    44 laf4 d$If$If0246:>@BDFHJLNPRTVXZ\^`gd&J$a$`bdfhjlnprgd&J ,1h. A!"#$% $$If!vh5 54#v #v4:V l t05 54/ / / / $$If!vh5 54#v #v4:V l t05 54/ / / / / $$If!vh5 54#v #v4:V l t05 54/ / / / / $$If!vh5 54#v #v4:V l t05 54/ / / / / $$If!vh5 54#v #v4:V l t05 54/ / / / / $$If!vh5 54#v #v4:V l t05 54/ / / / / $$If!vh5 54#v #v4:V l t05 54/ / / / / $$If!vh5 54#v #v4:V l t05 54/  / / / $$If!vh55p#v#vp:V l4 t0D%55p/ / /  / af4$$If!vh55p#v#vp:V l4 t0D%55p/ /  /  / af4$$If!vh5 55p#v #v#vp:V l4 t0D%+5 55p/ / / / / / / af4$$If!vh5 55p#v #v#vp:V l4 t0D%+5 55p/ / / / / / / af4$$If!vh5 55p#v #v#vp:V l4 t0D%+5 55p/ / / / / / / af4$$If!vh5 55p#v #v#vp:V l4 t0D%+5 55p/ / / / / / / af4$$If!vh5 55p#v #v#vp:V l t0D%5 55p/ / / / / / / a$$If!vh55p#v#vp:V l4 t0D%55p/  / / /  af4$$If!vh5\ 5x5p#v\ #vx#vp:V l t0D%5\ 5x5p/ / / / /  / / a$$If!vh5\ 5x5p#v\ #vx#vp:V lb t0D%5\ 5x5p/ / / / / / / a$$If!vh5\ 5x5p#v\ #vx#vp:V l t0D%5\ 5x5p/ / / / / / / a$$If!vh5\ 5x5p#v\ #vx#vp:V l t0D%5\ 5x5p/ / / / / / / a$$If!vh5\ 5x5p#v\ #vx#vp:V l t0D%5\ 5x5p/ / / / / / / a$$If!vh5\ 5x5p#v\ #vx#vp:V l t0D%5\ 5x5p/ / / / / / / a $$If!vh5\ 5x5p#v\ #vx#vp:V l4 t0D%+5\ 5x5p/ / / / / / af4 $$If!vh5\ 5x5p#v\ #vx#vp:V l4 t0D%+5\ 5x5p/ /  / / / / af4Dde9\\d  C @A(btx-structureCB11-1b'ɩ;e1IH7 n'ɩ;e1IPNG  IHDRLqbKGD#2 cmPPJCmp0712`cIDATx^Kv#r۞Qxnx~ɤD{OG@lR W%zUcw@@DA@ bz@@d,1!!"c/켘!!K @@0 ;/@@D!!/L 2΋!!@@ bz@@d,1!!"c/켘!!K @@0 ;/@@D!!/L 2΋!!@@ bz@@d,1!!"c/켘!!K @@0 ;/@@D!!/L 2΋!!@@  @WW#߸W%ox*v׏*g@'%D7mlE~i"Bs D~{(ަb?>-@'N7~lh7$Siߩ!O 2whD@8Q!M 2#DGR9B ~L ?|%';Q[x\bg;5.t{a0?+Ix@!;B0Q=]VQj-K?ME%^]4sm^ .C B.rx;o/,lsխ޷mr; {L`sZtH/sNwԛ b@@dV%,5?|QiLuF{YL@܇@]Տ|)~V]~?4럽t {ɩyʀI;n&ޓݛl^hJ/a/\r$8Vڮ+;mD/B BD~eki}ܢbWvqFUJx$-&+NTlNl/뀎l%o:!!p+ح|vQktr}p]7Ӥ뭶_5N@dFpcs:oݬb@.sfֻܷc@M+訷ͦB({<~? 6CݢW2M@vc~ߍ{[.B B Dni;UE\h[{ʛ8R@5-şVsֻ!WgĎ)X@DEݳ&j)쀑bǺzE)! !䋿قoa\br]7s!T!nO%3 7 =@@@d@@!!c#L!!G 2ws@ D~0 @@߱O!!?&14!!w"c>=@@@d@@!!c#L!!G 2ws@ D~0 @@߱O!!?&14!!w"c>=@@@d@@!!c#L!!G 2ws@ D~0 @@߱O!!?&14!!w"c>=@@@d@@!!c#L!!G 2ws@ D~0 @@߱O!!?&14!!w"c>=@@@d@@!!c#L!!G 2ws@ M|Vs!׶rmCFP@<ƞCk!!p -~οدLc!E 2K뗚fԬb lF!/N 2!!"c>B ^@^ҁ`?-VW>,OѶ߯Yl+ŗEFwpWbI#+1z'8?[ҚF}JӰ_4Ӯx@SȡﻥUZG޲oe⻭)þH&-@o6ѹjqFENoqN){wvk:4!$C+a_:{Ԋ.F]D|/?}? e'/qV.H/^="#ͅ@ Du~7݅kVnO!B 2vW?VF<"d?殠x@H 2v#3ν|Zޥ t!"c_3~4!/@ 2N:bb x?i`nj"Bj=cpx8!B|2_팢_˴!"cwuӯ)nȼNWW'%{RIĬ!X6cW7^eb @oItGz? ͡hocL{!!p@d~p";019Tcou@3Wk{?LcSǔC BY D~3Sqw"!eWM!OH 2vP77vQb{ :m@_wW_{+4!oei.B %BT7 @B 2v(݁n N 2vx|E7m@@'W<~;6ڕ<~p nE:m@GxGݴ!@d,!! ;/@@D!!/L 2΋!!@@ bz@@d,1!!"c/켘!!K @@0 ;/@@D!!/L 2΋!!@@ bz@@d,1!!"c/켘!!K @@0 ;/@@D!!/L 2΋!!@@ bz@@d,1!!"c/켘!!K @@0 ;/@@D!!/L 2΋!!@@ bz@@d,1!!"c/켘!!K @@0 ;/@@D!!/L 2΋!!@@ bz@@d,1!!"c/켘!!K @@0 ;/@@D!!/L 2΋!!@@ bz@?o+Giĕg q}@SZvV;[mWQ7}L|}?Ƣ;LmIsaƴv#]𽛳t4{;׽%2*zw*wmh]?d#UN.]PLÝZN(wP'4ֽjL?%0k%|GJq}j^v~%C= X|GD|ss_]y=u7Tans9 j/yaC?`)]Px&)f^%1͖ZZ9fQ7w.G:R搳nYdoӹx?wP"6Ůx`g'1B L2v9>FfIr}7%ύjAv;r[w"ME]j{#tS;臓q]*}\WP&/ o7 ..|] ]l@!G* 9}!1B#n#g!!w$#܏l:t{G 2ws@ D~0 tٌ%B K x<[~Ǚ@<ƞ%B BJ+%ψC BDșJ@|<#7"{#gf(!!y"c8B ވ#~n7~_ןNjJ}}c̾CYTCљ;@?ꗶnr4 _QO]jPa8JsA6cpZ54ڌ9 $@<9AtȪOgRu)pP{ά_X`N'~.6%l *uWRZX01WKܳٹA_<I0{bPN# JIz\+8' {B#ƃӚvhUE ?+\-JE _Me)+ly^eڥWw1)ɿ626F&%vmɸ5_~ݜzQpo):4^uq2C,KNRr4WϺN0aRįy C[w|!!c>Ъl}x5Ϙ$h". /5JԖGlpɄLV{ijcadpf%=-1c="q^ᓣO}zbhhj4kT϶ 2'Gȯ!S3%][Pu-QꑛRe@]9j|&^ 8UpXgTOĻ7A_!/B2VJ6𶉨iP\HK0Q|>OoQmHW`2mmnizljZKEKuca!uSIP}(;jRi7v5NQeG:Ј9.͋rYr{ "7~-Q4Z*N`r ݬe Em !cJ@,\3 I5?gFERkPyTxKZ>aN5Q}.(W]A)V<v>>m;M(5DhM8UfD6ZVHQQ"0즯36;b-WI}P,;ö1EjESm{X{B ^#dپ_Yj2S?Rz$ǩ mm_dJK|p߸7\_K/}OAb1grsW WobP*3[ [I0YDJ,ИvފHTG~WCmuh[:!݆촲˔eST_ ,+eaB^%,t}A6'ä u;B%wS;4EN-B^9èAIed ^,Qgh4ȴLe*g;! !cLPQ&KTjq TFqbU>ac毒bjJa.V}ץEvh2(׳6jw v DP\r1,j+8D; ,~U_J]fuRЪYOl"q.e75ф{KwF5@4OUOˇ\3@<7GXebfʖ(:[SE/kҕ6碜XJ~5Rs5g|QTZ0k-q2u|@Vwd^ZP \ZESEwD2T62i'*X:|Z{6L[3Mr[rOY/|Y QIz9_ET ^5!L2&A.vu¨1tM(Ѧj*gM=jyeMPG{$~Z>9s6^ d7-j[96m[ !>Ȳh2¡$u9wU[,^c؅^U)+|Y''oZ{k`*WN6i2{b<ꧦB ^#dLRż5s2/▎j+#[ Y"5 o$ ea?/:\,{IF˄N-j@FدlxW"*aLSN<75v=NVǴ,-e|Ӛy dmXܿ6m4RHUhA'm`-JJ/hK5 ]A%%x! m-kwxճɇNqԪd<.rLsܢjR%!稵A\Z<)3beUIٟ98h>rp_%΄\ی1di۔5VWb-^ݕyN3!.xVȷ-:VnoHHնl:Je;^ٖnv7oR!0 u,t^G2-{&(>J<5,_ҠʡNpM R$i _=EY9ww1Mc UIC!KbRJeOz2u@@TNpPPc1Xҳ2_4%a 2*2!pwڍ1Ymz%Dɕ*7^U'zg'q_2)!϶ԓ∬?.%d#̼mֱYrv_sr[eR?AE/~ F&!u}ɁAwxI#p.&٣~D̮֯lY_I'iw t[}茡KvѱR,J2g_ϟjC sE \AS"B!J\mZihZ't'fK ךt:Sd'uÜ7_XɚGu!3tS3fAd$z(ۧSǮA:$Sb,xRˆa9[X'蒇^xfc|9B F 돳KlzJ:%I_o[g쉏mHe:X1bH/W Qe[rj)5P\PDXRtz D2%n:-|RD|4F6(:`;6i-Ք #dLZ+LQJ0 8qB'Ae*V0=:3/Yv(0WL]{cη (W82kW=NNT c#ʸZuA{zQ q(%sj7(Yū﹃%G+zjTqZZ - 7oDCw !M2V.򊏐QI:S\qUz8SRoUVa.GKp$DZ?5rjbaaHRw>l4;STg=ܜ ǩRewV9>?E\nȡ/ޯC)nҡ.h69^6:j.?N+|MUN@.GX=߂20ܔGQM+|Qݕ_v0Wf[ϠQ)Zc֛%AL\KGc>>j&wm6-1hC;S=H2s3j7FNFi 0 q#Rh6O*!BʯUussFTSq[`PMRСT|~tJ@܋#dL*rĪ`+0΄Zx:j݆ұrRs?3:־󿁢\K*cqƵp^-GT!W~=~BtP2[Xq6M?KVai7L03-x~b"`Ah`6HݛLWҵhccx7ђoC cdLIĩ4Td(nL\K KtBr?%esN4Y;ҷs(̴H<=F$J㜭?+093Vf|Fi1dm˶Vxfka8,vג<,qdײN'쯚%6dKk"eIwlGn֪ ӕ>ࡲ)!p7"me=bYSzR骨U_irc3IVJkƒ)u.EjyBUR:-)(,oAT.cp%oELwI-څ#=qHCd{2Ub+al{qB'|-CNYߢ2SRK_׵ K;B)eB!cUGh$ёkMWΝ3WґTyZ46S  &fcW-+w*rEsJNuSeya"h bOc|uF~Tg9Ou¶8UHn^2TFzOV K|G^{V{1vT $f%uV.hvb%I";.)Ǧ#|]N2!F2V2'Fm_I՘J[o8O:<-sվ8D_X׹U"얥dz I-p.<~*YsFr}O]il%/Z2a]Ԟ6nɰ$Gd>t+͚&7%6kޞS;T"[خ̲H)%sv!ÉW7`}5NY=31ά_JNe2pllRDJ5F sX?l[A1> =[hg á(i -An|#$kn_9kM촚gqVA.ƘƟw (;58ʦmTy>w{x-3*YTp Gn;T짇ZO6W&;Vp%Jb=EZ6g|E*$ѤexxZJ7\#s**S &w.CG桦nϭtn 0_^A駫U}7pmPq<\*ΰzh)}-N&⦀cN01mzHUJSkcoi2@[8}m(4RGEF [ۖΟ7!aբd댖҅1+ S,B`%[3F=pogZAkq%k v8KNi'ENN`nݍ^xɼ+G%o$Jb|9q!յ}PVGuD|\fϣȥMd0V357}SB4Ci 6 ˁ%l,ôqJW:`-/n^,HЕxm)@28Tc, a('=RP,-8 dIjjS] 2{4#(퐏-my 1pkmJz]ǩ].&؂fXd%\؅H6jwVoT4|GLfX:o8~J6Otwji+=JJW,;FMSG.PN[S#;!C1&BfJ>rL`BO׈VEceyhN Cu]D1&~Eu,ejx)|`(Sӭ*HdyI5Thɻ \whݰGFz;[ϭcO==r=+N?]lRYK27TVrj4u~ћ]Y,!}oJ>6 j[O鱬S<2U_S|i _{u—V25$y6A!FŅTb;aLQvglx.XITtl Sj'x7W Ofz/Τz6u">]C,IƴFace^Öa|[Ų.uIkO% [+nef>\FbseKI9[%2y]`+7ʕ nڪp]tʆ@\ 8szN1X7W-eAvu6FFJz7}0?Z!Rcm%kԯ55nEFt`oίq~Gn&?]߸-l=K-kj&obF / >`L4DxNh[qWsKC[ulCs)B"L1)`~ϧw`B16{r{irRH:SJ۴"1Ui!O'gv%{Q2тZX/ vۥp*?{0omW3cmFv4£Uo@* Y]fck@-]"jq[آ@k'r"#zߪE5?hWKIa2U{-cO GVQ)M m׎5angyguֆiVb-"判|"^ZjY:_ l+5Y6?b\%Υ_R#u]$ٯdܨd%gp҇E(U Vqړ.CŖ7KFƽpNs%:C&ѵIx)Ja2U2|%Ɠ1R4lM58F;Xe ?I{×xtVR>.67:b{<5pFf\C;@4O-wyLס4If^Jk{\[f#Jdn>GDp,.(8m{hl=%EѢXU,HjHn޻&+n#0ާZ^C,B.$gNJFLJ$)$/"(nFuMe=ɢn #KRd$>sLV())yڂNdHk ZwӵAFi)"ELWh׀>Nl7!2K~jNސ:DCK0x#Ǿn.VMS1$Zy׻=m9bX/׫kT\Vsh(mYVbު?oA7QS#Xk&Q} ~@M/kruA#n*.Jl\ fUsˑFT 1;m9\(}ЂO&GH\rDq̶մz0ա/% ]XЏHQGPN@23c>A3gn-d~Qbfd΃:dRNf/n՚ ] 0L)JC2Ԧ89%Sdz=m^qRV7m:@O*F沮?zVQp\ʅ&iz]5\-X#Xyc>;Ff Y㎟bw?#dgI/աVΝ$ fG9R rC¹ PqT;o^TaMz5S~4jdreԩ2^j/dK$%&N>%y ¹rS!Jw;w+@`G0/RE߀&Q`N'A!2;3%5̹{$Y +Ƨ z4$;\kipe)3V4|WЄ;9XvtdjCEW mYrؓ|Z Pl^ZpS4DѨFa Faa M 6QD׉h 2 ara"[˟_n<ͅxEoZ1V#{?ՙD.` ^kgj~JkC%JЂYvd֋]$TWo:F)=йgΕΦAڹ.?rw_<%sX as[JSdC:Vd0+{'֯k̺Z`" 7B7J&#Mϙ xc1%dbf0(6~p̏.yPg̎&Y\][9/zY?|=,R?0LFٕX"zw.g8G*PQ]aX BF̵ۧd pD=[v:2ZuJKKO!݁"!:Wf/A\WI#$*$!sZ퉐gץ:;x>w_Y&#dlI8[R@far|8C]$B:XWN@/л욖U~Gzr NrɪJ7h*'Z-/w~iu/~yrOz#dLṄH-ޛ S1.^C2/gBTj+n%v9s54Qq.ÙU&J̻J>iu}>޳T8W)VT>P$qdrz1.=* (@))) ԇj"Lc*fSIa}y'T~ ɓK{2َ z>[XƤ ^GGBFg'U+wD Iɵ O@ƚzAysQR-՝5yB)YY3ͺTaZXʟFlfY[*Nmۛ܆4 = e'ղ5借MFZa#:{p8y//mZ!u:>ǏprIPN8o !OJQ2W30 )szZߛxWFx#a%Y^9MC(iǜh=)C+[gs>"fu>.%{^DCO2|=Q.W;)]LmZ/fFEF`՟\Q+N!(nKS{ {H-V}{Qk]ylO&-W;u&6X>@GX=]Y_p~Qڢ0k)Ou}@t~XQCі?b͇[ڔ3G[feWqMJQ´]Ri|L-T.J d0Tfa r=.DY{o$&~Ip]zyr{՘o;r1تmȝ42GQRx(XYcn9F@4旿C ^dl$NBD_*DOZLcJ;>^C$qwre$VΡ{d]pak(`%a6 r2:@hzNMTI~^ )ll=zb>jKpO h7XEWpKR84W&B9w^fA!2TV?! Zy2@;?˲R|̴l6aL4c}e=euUvW_GYyJ*SCt;:Lm %%jZbA`{jңr1O2BkJV/Jʻr<ɭuҟK޳ LP>@ ȘOut6r^ uTT{Pl^tM<9؁>< g|itY+EA3kKQK Pq<*̌PڢGm, "U KGC Q0R_Ts+I-j59W%5/N?%fUĎɧ3HJ<8}V<`#7}7c^VR;fӼ-ahWU`)N-Mqسsnk`DJ:?cD1W;F`V`쩕7HN`JxEr3ZR 1S+N!!clr q:"C26@@J 2xav^L%B B ^@d셝C B "c&{a;X@@ d7voi?B B"cwC B M 2voi?B B"cwC B M 2voi?B B"cwC B M 2voi?B B"cwC B M 2voi?B B^xHU`ʧzH;xE+[縌mKxwa &z2ElِܑKʲM䕱 {)!E垍mUln?iլ{Kok.yYpow]@x5sKM?ԇmך7͆{?5@**o݌oy5[\7{g^D*svUL-l{l7 j1 k)|4(TKcsX_m_/ۛB B^Q:~n.|}ۛj*:#3 uNR2B ފk؉(uYdl#d۬cM;(g"j^Vط &B xgcxCUxoqgQ'?h=.>7WCtƶE'r63&ZלIlh#&3\ʅ@|B-WߟT\*s컝avjx)Od3I4~I&1ݺPCP@7K_?b:5~쵒vR/B  glSM8y[@t=ֲm.?2Da"!!>^Kƨ~xC&nϘsuU(1T@גl-%۸ 'T9k( d@|[A &6p7hL˃͵ol+s=%ql"ǣ>!3%b1l߷8+YK˽չ7HvZt/y*..B ފrwI[N1;כ3wO6M0[rWa*:3Hvc;ywǟ\>_[=7Yc B B m^UTlB,*]Wt6抶U^8cz@@9ȝ_Ӹy| {5man5o=PLr4토Ow"2g>ؑũ@}xd!!{mp ?B ^@dC B X~c+x0|,Y MߤB B L 2`.B B7 D~f x0؃$Mi+B B"cB B ~#~nWOJ_?1ן?|}]^ٙ]`5~Ģ5& Q^e0Ͷb%Q2 6|}4f\$e/@/qRB5_CWr3!u?q4W4ps8Gbv줥݇UZdW3 wVʶ{#΁Nf'-ȖQ2R+4-Kes.06mwQsci٧fIlzH5]9 vf4EO"D{k?g FFz_*WGzy|dՎ>O^l9j˜?ԗCpq;$DU|7AFu*6oFN}*RTE= :YDF!D?XT8&ADq8lx0jWyTz7e˜ a!gV!#;hs~@] >Đ5uw@Mғ=1u[D7dXтXҺU*\Ŗ  T.lm4˼pGVk]m)Zd+Z;fJY^a{3{,5{瓓IuhKE3\^6} ifqp!2tCB L12C#Btu,^47ӫ+'HVO:De+3lrX>i'OLzJ3QS3,F:ZtX#DU}8[I'7 JڍJpэɊ%Ƞ aqnߋZVb6DB> o䓹e1yЈ2ČfG@ }3ucrJ%Ivop"wMl8>YFFZmR(XżΜSI&THBF<|߆U>%brbs]ʗwXXVF͎ 4=,ۅ#W CdLid:DLd!G )188u8KT-cWfa\ (쿸Y`0ypK(3dhݨ L-X ô$ )1) Qͅc#[:=:"h 71c=,6l>" % (YTȕx4uxT*oiZq\ 6J#d)ynOzQۣH5x ̞E\N6;8k&E慃@1=WHܨsΊIt8S҃du?X v9+4V[AW"c=N|M|4U  + [i6 /XY#K*;rnU똊Q9ٳtF13H.fWeKT9Jr2 kgBzfnY&NhH*=i5}$ha/d̼TgKWruDTɫ%GGaKӝ.Q9\Ml0m?A&Jn:oh{M>/V527ƶtQkŢ5Lm^h&hb gdۓ߭o*Ҁ]˜dt#‚B|ciCtPۙ*%Ԧ:? -ULzs(ڳu<)B lS8yI%Ǝ5<ˢ\3䠡A.&0yrJp̊ۀ|^GRl֢vO[Л Z9CLBFG4\j1ஶFF4$1WR* 0[G0ǺF41EWp u_ eH8fT/& =u2D'?=RYw II CY+Ud v)tEoʲ/[ݾurYm1ˍ-ʯm FzAЛTv{8gӬwIHQ6qxF 5S\ՎltgͶVm֜+/BWȩ?Cdk,/s E1ig>HLY4%ʸʹ"[mzx[XDwdSO+Eh({CeX&"%#Cfma0dԬC6AYaDW{5,V)Hn[즤~iܒs7)~DaI=Ƣ5!\™ uprV,ahқaRVؐR;Jљ碫Z-<2GՌp>xYh\ Uf5)<*E?T[|km,*fUM݌UK "۹lB''e mDĀMavZ@1'J^zk0p^=ŽP4,$}X xh;Qqͧ졜/5х(%dږJ~3m2{lbd),+>mVaaYSǓU e w;Xh$a < v֬3M9;'UX`Xr4nq"p,nUH̑#:׾!T4_ǦU!R6?#d9דB gN pؓalǬ2-|8H#q9bIP1.Jk+r2z.@$8gpFsN3cSdNx3?$ݨHJC*;Ǚe< XZ.W}LksԮDEr䰨hMfb{$FO!$PTфAf%No3\qGѢC^PYBGjN_#QQVO^́#qp=I )֜ѤB>f#m,ߨ ʦ7 ?Hٱ*IA?)w cH3lf(^c9cbApt]䫆sƳ#dl(ZS2*ℌqAi^"F0@<0S#0+t)M bg ٲ~MOpI5|1&W7k ^\Uez`WstX<нek(0UlMjLf%Y]k%T +fbUV-zwϐWcsZ\lR6*&dX '*66aPp&:>3`\%q3!ϑş g|3&uY͢rmJ6g|GȘJL~F9f\ "8Ϲ8q`YZ`: j? 5:ĔTB1۩)U;A57K(C7Z&'-6yV4h,!YcI@[Lbr=ӂJo0k|Mm~jc +Ljh6yj@12ƉcהaASLC)EQVDgL5|T3b)4Vٖ8p{_#ͦV-.u5ּ?3VUD.w5XXS -k*zД ~ת{Zcxu m `c"И}0vV9"c8f- ,, gy<)ӵ`dl 41Q~1VNPĭc$9?AС@pbSR8ĹliT P0hx\&4{Pm.lM{٠4 `Xa\FSVZgLZI5d%شE_!7b #g HxSiOk\dSQ)C\a,Ui3 ˊ6bR95T*Gb)=!t9(;9ċ#D4<oUVָMRlf6Sxf;K鼹ܵu51XSL@Gk8AlHݺNEKH^륕g} I^g`՜|.ΩhjVRMjcf :%簅 "A:lg\ oOK(T:l)ǤzsVkWl',mrX< dLƣ`:m3z߂AAFmZzt5"G!⡜̛̘t3#_Ƣe4kQWmg4'HsڴG5;tz.6S|X S-6!ye22o!s2b#2nB,ƩP=ڐ fnF3 &dPR] &0Z}rQqAPyN Ӂ6魼nShT\뚳lLtvFU 2IUy<<*'G,<\7[Ӫb'3L*R\ѽI\VD5Tkd9]= A?wns,m⡱l-tļ RnXsœvuD5W`o ljӓAsqES:^AOq0 q5}WCdaåEc43 Ux ׎`N nj+H˸) + NHM]ߘl\ ~m|VXCp91114 gb/eQl` BM`k7ÔBhNc0HqMp:I lԜAh [==[`$]:2 +8f1">)%?| 6dm rE 1Tb ͅ,g2+ Cjv/GXVN5I@a732 l][m -'u#>uH],gbky9c:7}-?Wg Q2Vi e,؝59S^jG{^#gai JW=)'&9+)wd0{++@aH>i8G qLIND٪]\ '2,72x*2YQ*6š HVb7O6WL 969jYN \h !PYf#LXvp? -H"cUVa:MqqV`~~(b wYLna Zrq3_:7c)50dVK]\)FA ' GSP -F.ViI3x%'<&Ѻs?5p0}e P+ k,6}#pE ﮏeꨵ8[cdLb} Hm-hvYr8X˹߮%Zkì*bbTFn5ͽMpP/ig;2%>qc:ث)v,S%6:I:@Kl3֐N)o7sCf̣w%mnYܶjQΦּ-u-z lԢ}(Nj0h;^88m{'%>̊9~O2D+T_[8VXg! r3MQh8Nr`;W?gtNՍ{vo{W^hϰdyÃ.(q(B;sCWSAmFSMD,ÔxR hRTGFE,|g{9kC!5iz=%d61 &>c8${NXa|Hl5vc^^GC ԦQNSĶm)#9dYUlQv fIve E6Pi-WemDci}ۦرve~N^ITQ͡,i3*װ]Zvf-;V}4Hfm֕7(uiRU95,0S(2OЏ-eQٖӎD耹1ݻ,[7+S~Cd`I .37eԳ5٣d-؏:> K&4B -l&ZQsCN9SijvVIX%wIӔ}M FѳE,hj7Y=:Ʉ6#Z5isBj#@Zw=*zj~q_.8n/|*\iz=`v^bLKcF];&1آġ1HEDA }Q~isBXrР5 ЀZhvLfI{ (&sӍ"mzAneb%>5g/$_f#GpǗQ94 x/RBX }!6'e(S\qto:X"H"?Cuڇi_ hɜ%on6 5Tޘ0,C,k.c[ZMU V-l'55S5CRZKJv6k錳oNC~e{sb-qɄ;yHc"GiEw=.ȭ:9q0"Mrv[ux8ڎþA}!&8 zFۤXcLjʈ)=*kxVg\1a ˆR\8-!4m1!w\t~:y$HaҺ%Ō;؀g]P{CՒ#;bҠŽ/n`\ECs FE7Uk Ǻbnсk:̶a*1WrٴZYLӘԌf(0&%'553Zwu-CP-dlflAf?;9.EujsS)2jַ߭m& 6YX_+cBoA(ԘB\-Pl/@eXFzUMr TNodtyIA&۴"_HgbNRN6wa5;T4ЊM`)U.s aJ=r\ԙ^-F UY$BDTfEd\&-&mv=ՆkjH2v( f8Zٱ[_@]эZsAY4S̷O K=UC Y|\rU04R&&C{֚m Ƶ* SsvPUFP0`-gV0i_9"kвjqѶ9fD}'+X!"KYA'$QbQ88+1UNa%?eM>Rz,wDҌ4׎MISB/%SjMٵwp4[t xh% $jg;`5r=a tM:2-0IBCNq=i9qr[50}Pˈ1%jl 瀂*8(4پwUF\R1ccnpfzʸuUNhҚ &F r3:|ŋ*T-qIg*0E#cs3s)݂wPWU,{Ý+eЌŽ YPIq1&pYaiզbxEa#,[~ ,0Iv`*|*;3s"IR| ~Z@S6 H8QP i/ϱ®ex(̧ 47qJ4s(V WC(c6k 3z@_5PP^ϔGOhPlcs[v+F4&ZH6;hB!t吜ק=p8;:{VpP۫Jlru(yiR󃫷FIR^Cr1b38r4z+,>vve:wd46vcȘbF`|| ε1 s:" #Y D+2!bE>^0'!p㾴zcylR} NgśP hfʣ*%3C$87T?ZԓAL41U *,Mޒd#N8It[EEC(GX &Th/$@)B O;K+Ql,$H Ul5{#hacդa]5//h笫.4sMΚeLv[&ZS2aBͅ^uN)g2YMqype`#);e t5ƍ:塌Jegs'*э|M["#~vg#I¥3+Ǣڰ %d@+%!Ro_*rFj_*)V e4E2!\Hu2e]bVpZԣ3 ;ERN*J&S+Ut.n-TvՄ WEh)S-DVꦢ1.7 E:ߞ'o"^v-p=H-L>A`߈Xɥ.dT3*#r1t*3CU64>y @RE՝xVB% 8brY͈+5(3זo75f$=o9=(.Sf$-y*WpL#6F>D=M#z]UYjlα4&R9Cfzhg8?앏1kd^A[d5XɕYIv 'bK""|-aFUJSOEChAkS)]D\Y\/oJp8ߚJ!s(XZ4"%kŴZ$0AZX %G&TT`-i)&64eRG@Kd4RҲVG< *N,ˆk-Y814N.[g.e>2<.8*x \v Z1v^!eb2\ p}:{i1Ƶ⪆̦$ 89T&Mn7h.yuvlO+ǥ)~&rm\ "m*o ro~!2& Yk&pb@7d0 dkP%]C,j\x-14SlIhkk/B9KÚ\"C`G9)Uh$8@\_L]Z`R)b[ RB6[²o(2.s. Yا(*P$+zv),gd(sݥ7Y0mZp)Ks_;QiihI%N4q?ը&$vP;rD(ۙ`-~JAx[jQΡW }9J^DPVX ȁ^ᔑh.np葠v 5`׎C^]o0Ϋfx8i_!2)?3sRS s+We]rQeN\vi<0Z`gPQ-(hG,}.7Liʜ=U#&ِ:@c0 9=OE>46aM[NAH=0ӐJɅ )/0\%P(!N*٨ [y p),D+Y nNVĬ2SR&`}BYc֓=0ձ\sț 2c !6aϒ˷r[:6"617 ټZ˩t$+08xNp'QLM 7f:b[Kpjkh k݃d!LrLOR39Cc$Xs(cyZ?ZSҎj{B2s^G,=LVERp"U ־?5iLJ ɜf` p41|WDֆSdxXё N)^͗ 3́(ړ.MQu7¶ԢL6vkCge)Ta[fV pӟo )~\9::Ck6=isikQ-S ܶJmtxvQ*7z(GxYP"IUW4Z"Un@\:lm2h7mׯ~[f_gCdLSϨ0fL{uBk ]ԡlIN'ǂb!9LjasתVfI D  ,|Cz'0 6 V3 Et8bLꚫsN($I:0 z>Y2'iA X!VJuNQ9^)_I Դi&p8uc~EMԫPJ>sgUUgjBD.osP㚟 :؈X-C5C źP ւ-jj?0p@?t٣^ οܓ(^s`|-"\ GôpvW0?75w"c# y13jqΜ)E?iPXnerG^pWbԧ@5g)g!(@O|VL _ PqnCTA~g6uTYSc3pǜAYͰ16` 7GV0ڙY0HJI6N MC7NNب'vKf4]cq .Z vkrM:9p Ur SK/p<22IosR+zB5x "GǎZ O[n>jiJ36.5 ȏr);tCq £tE1jM`5ǑAMNdX!zץGeND޷[8/.g[?W9Q!2/q%NZ5#=))9 Kkw%gN(V@KR G1) (Z򸂝>̀(G8gvaވ G2[d)N 9WW̥h aV6 $w*ij`<7fʁbH"K-!^cC#-2ِ>.'t"X)ļgT1bE1VP\ZΝV]{B[OyѝiMj`-IJE־JͲg K#>.&NUs o2R O>{,8_A;.z[Lws(v*t$|^Н;sY6pT!2P&,H6Lo c}VyP)$HbO9jH-z!\lj,Oď{8$ڷOWA:=VJ\a%NC P0EyϰFC RwƃKeOhrt d[r5Mz6V**I3=e(Hq"GjTۅ%Ӕ.h'ب/qXm%)3ۙrSu͑"gtkL3Lv%%9٫[O2mq}Bˆl\Kطـ~w#Kt rCoN rg+ Cb'9[8ʴ?hgNPc"0:kFliFrDr!id[3hN n442LDGsxySܛCo[l :`FگԸ`uN9lPI<p#J4,q':xCװmi*!M7 23JK{:@&B*B/X2RY e9s ҊV5(g CEn6p'6g=,.IٮB@FCOȦz&­61(3e gMIMjԜrLM]n8sf;_'~w\w(Ne-u](AEU<L=+KLULY][*q+XA{c`h`r.|:ƙx*4 2cB})6{I[<=;cj*4kORud$z˗oYak1fI5Ŝ('t\%,t?R3V3 CGh1l%6rr'{EC+Sb}\LZ{gqU֭'[[bUQv,fƱm խ'zIvSHlKafzc̪̜p!ʤc]Tk?RiEf-3X N}agI^PU4Ԭ#F3IY%تODc3(E}/杌ZA;*>f}/mokmKca|px$ªV Wu)k=Cdk ?'79)nJfʵJMR]TffB*1FY+-j\C*ZH7HѶS{L_ .~ѷVcaka~ x)).jh'*ӎPFnqX񍻜cB:0o0W,lV=fj]P-cs3chp5/.k8rƩU ԦS]>i"~Mvg|Nt]i<3{δ$QU#r/=q!2%zW/Tǐr(8fG&Eq2NR9V3y0"1J\y2\ R^jRsUR(N!!)kJ-Lkh kkrf;W&[ PZj_mTMr,kO8cys,ږTK]"/IrMDZa]ߊolʊULt|ܨRؠ[wo oͮ-ZiFqy.Ęjc*vIڎf2?i _7aBd:Og(7o/('2 -UgnG~~9<Z=Q9;6||i'׶ 9 j5LRP1:*_>ՙss.7sGZxtmSHuF;LiA1EϪsɎ$ԨbMv *0=d-l՞jspPq qX(hFXRn.E1X0,BKG3VV (Vw¢MSZch`Hluw꒦j^4qtpn#ʉ\6'/8XiƔz3l?:AsloUWGk}n$2O96'y]j?R_6- ={t:ddP{ᕸG;F&yv%K±['-.=ը7H+"cy fwdV0987+GߔpqzP-C9tR5n+j+ć~7ǫxj\QYA=FƐ=qNkpW E\%-NLm( DACٛҰe;g#q8T^ardma*ϏN~8]tQs8LC%a nP'Զc]4k?kUt(4H(Bv?-%왔$qF Wjj9P}MS%Qc-׈L(X6;!Av^sx4Mb\rSsbaMfˊnͽfJ3UwXhyI UӺjgn4̚s1&:oz&>T eӑĦ2Q'<pҐ6sFYr~/gtFe(t\iĄR>D[ʡHhN gϱJ & (L'F{[i%:,q] 3B)[D0ҭ0_PAh3OeКkGȰR=$n:3o`0Fᔤt&^ i2N(Iֲdh4t|TVZZ[Od{S6teV]2lФ$<grup!Ujޡ%ƫfAIV0#qkc5ϓrW< O;ͼӽ59zrB_i`aҳX ={^wA#cD<0Zҁ?Ld/,١}AIe85_9{ ā2@W~̧K2}@:ߢ!F.+5sx;K*8le%TSk2pr5v},TL$"4 L@(5.6MJie*ɕhp3qW'Rsv a% Ĥnd5YL"apYetdY撻'#nE zVHk.ǑU1$|p:}On˄iBjJJ.}0\l/"S7Ƙ=y89V kUDl`&Dh}rM MMci&1&r#S^>8Co%8s} »q'onF+ SjLT>Pb%U(:sXRYQj6B+,<.ea2/Zq(YeAbA#T=XͣwV=/DZ&Q*`5jӚ0:&Hn9@ 8YySìJ8 @p M)ONÇ5.d9{NُEZYXk^S>'\ݪ:Lc4HP@c9`,~Ez,Cl` eҝI^nqnx@F3}MH@~: zmfW tbƚ2P1CGw{e.W8%4"Ҏ?Cdlz`ύ4Y $a)6's:aSuBv)PvBiIOmrĨBLSSZ* 1 T@z.8QNqSeǭmxk~7&Zl yv>죾)7J`1cʟ%jsۘՉ6,Ei ,3 f@ip][+D3+ L䠵,( 1Z\x۞4juJo'!R^Ze7"1X>|#I2ҌegTSٴP0 }Ztc AI^U;5 Kc~Sͪ^V,=LOǥ'Dž{}|:A5+%,f$!_4uːVCYdhwyk0!nu\Yy(7e$*"Wt"T7F2lWu`7$Q)sd.lˌe۠ C2eXS"L 3ZL;WokfW2:ЕڒTi)Ne~&lo ff B[/_KFێ~5 __h ooՐܲUF{#{Uv,mC=\ЩfG:؎g=|q/n{^rl' n?Dy3E0HpNԱYs0&Cq_ hBqX 7clwHEl )wLcNkn͜DaeJU' V jQ9'rf;+ķ]R[V9H?g)*hYlĜ#*#%mWm}z+ B 9$_sQ1,ay>c&VtU (DϮReNW#FDQEߚCoOTy |^! qG??jw^zߩUUĽ[ҳY?vEܱeU߻L }15K \:[xU~6frGYCij=Rsp Lʅ2C^w)+{'hLY:Tl?phFVNZI@p] rL ))3[4S $d/Qh@Up5kg4E ׇ6rD3;!#am u:E,' ma ϵg?xLq;M#4a^G.3 GmEZ65*as敧鹼̹* QɑZ'&'O11 i<Թ˂k1҅҂؜0Wlx(zV5GMIbwVY]~ci^PV$UH0 Ni2124Yg1Rs1s ՄYGAνP=Gu5@+^MyNҡ)†tKi ê\5fvĒ(`G2J"0]ǞB>D&EOW$be`k&1/5"pذ\4n @)7/^>SUARبϸ@YLճEStLA)Eu' *g|ޢ 岊+jqY)\ɔpⷖnfM@sѨž0+|Y]wlf" *B(UMuTܔij1$=)ı76F[H eMS>'$08@uuNG=>jLT4EL+f``ep`fBŕS7Y`sBbO 7^} V/_mthH9]iT>'7Pd+I!&9P.Jcpj[(ݜgi[߸,ɤdK- 3'ފIIZ;yȡ\>*1{ W([4rMѪD^p˜u} _4dGu/|\aLktԵ&KyO.{sÌ-1+=?_q/8(yi6[Z*=udyk_Q:-^nZr5++Uy&f}7h =C;^U<(;KxLcݵC:L۴ֿYPbl 7kg,=U԰s^Javwg,4.&`{ͫ{~"B ~r[ϼ*i)B B L 2Xxav^L%B B ^@d셝C B "c&pGW?_8bz@ ; ҈!!/F#sC B ^@dC B L 2Xxav^L%B B ^@d셝C B "c&{aXb B B D^y1=B B 2xav^L%B B ^@d셝C B "c&{aXb B B D^y1=B B 2xav^L%B B ^@d셝C B "c&{aXb B B D^y1=B B 2xav^L%B B ^@d셝C B "c&{aXb B B D^y1=B B 2xav^L%B B ^@d셝C B "c&{aXb B B D^y1=B B 2xav^L%B B ^@d셝C B "c&6;7 mtm  ^m\h72:0'Lߞn[ZWإ&/ .5E rwqn]z_r%E_B=y)&1 b~]b[z=Sv~qhi8,ֺя%bid7j!p2tA͉]E_BI t蚲GL8B 2vRʄl^ן@d,A!!9'pZ֭zŷ {s/XkHg\sTbv׭[9d O0dᳵV7s. [H]lq3S˨>u'TY7˗==| bz\?E= fNobbk-.r?{M,5vSwV>W茡$Нqv]4w. =QS!]۷3_WQ;-Nx6kז#,?漊='gsؿ]xbg3olrtuH&o7ϯf/HZmOn4F.؎ͥ&cQ^o7mcѝ3p7j}]U|LR/Fq_,+fJn7fNXC*D"0d:IerjsvcAyzQWYMjowOL3G ؐ N O{9"n6+SȾO'1sRL -AU,!k,<"1e"smg=1ɾS-U&4-źy tgfb)}ntkGIu[3^s>=+ţm]碋9$7p)v. +Okviyz61}1^ `[>A8٫v~5..͊ ZKƮRs_YQmmT#=վ65~av~GT*h*};A?JO`r]mHmk/mZv)p :H}dbG捃|n[e^g[\'*ٖ4yiqo_ͅe8[sbžz|Uť*낋!U*raImDZ17y7"v]5*bgxU m ɫPGҝ0!DK&N4Obך[xw{д7:ozd\Ёv 4S[.px0̗tl*GjzԘ~_v/ƥ+ \7:~>j.$.Vg\g$S>LƮ>I,zIvv&_2H_?s )͓ݳ]{[.ˮPwW'{o'yN'|]or ~0w[?(WP"é;n#6eڷGjsuu+<00=.,W/+֓WG|mAw~78G=nVՄ]"KGp̚dοwf/ 3e眻TBAnt8/&c{;_m6ZMsKcO/T<>+jfQ'ƴc~kGV4pjJ|^;W;*cRxK`/hk6.u9?9tg 3-gb屙RS;d* R>I?5Bww!`8#R"v^'D^\β(>M.ur=tUoC²8#cٌ+.%Dރ@d=Q@gcC\=;?ypR̡Sο{xuy' u5֟'7'я|\wӱnt.v]Dd>Gg/C C8uMY.ѿWiϰ4ݒK:_elgvȽ+v\Szc| mbh1U|s>⽓XjSOrƹH=橦˷}1Po1?l")3*֕p0k StRk)nf9 G'ucצ{8Ц[es[U䙯ߤX_stbީ>8wKMY{ 33䤕qT g#|ȟ#Yu˃h ^)cg[/ҹzSI+)uvbڏ=~DeKڭ /m^ou;39]k?#R..{K$_2誚"u{ tz!FE. 5ww{akGխm^@=˅.L]|®[4^:G]^ -5\^_gaJߝ(M^1וƬN9~ }**cz}5JّVZ?gړܓX3N 3}id϶+w}A[(zmܓ:@}9(cy(\]e=7Cwe)0v0襧5MAeL~m&IS+ūFk[ca]1܏/2&!眰~H3 /+Gp)95 %P?,?OU3s(і~U/m@^on{m@65kf5em{0ϓk_*Ζk>zrfuSn֮E/_1ގg؜Ǧw6K^?QK*tilWcnSyK Mu]anؕHRi|-s:Tlr]y㦄#_>~P)s_WX6y{#W{}=o y2Ǵ8NON&Nqkmo{ʞ4vlSSJ[n]^nTp篚1v/ؙ?l썋H4bS 51mϬI\%Ijά^M}DzW[R[3mn]Fѝ#pgc";?U`N<Ϋ+]ǓOIetM,؛\mKzkɹӬ}q?NsMjc 7ys^I'&s·TË3YǴ|]G)C ~LBc[CŷtdOG;TOgz z%WVl "Ѕ, Y{!gx9R~6|2˸*?x(hc_oO`෇*4!n%"A GPN!#}l}#N!!#CM!!w';t!!p?M!!w';t!!p?M!!w';t!!p?M!!w';t!!p?M!!w';t!!p?M!!w';t!!p?M!!w';t!!p?M!!w';t!!p?M!!w';t!!p?M!!w';t!!p?M!!w';t!!p?M!!w';t!!p?M!!w';t!!p?M!!w';t!!p?M!!w';t!!p?M!!w';t!!p?M!!w';t!!p?M!!w';t!!p?M!!w';t!!p?M!!w';t!!p?M!!w';t!!p?M!!w';t!!p?M!!w';t!!p?M!!w';t!!p?M!!w';t!!p?M!!w';t!!p?M!!w';t!!p?M!!w';t!!p?M!!w';t!!p?M!!w';t!!p?M!!w';t!!p?M!!w';t!!p?M!!w';t!!p?M!!w';t!!p?_i9~6~+j^cgo€DnWqm:@<ؓ9$#/Jv TJ3xgy6}<zB)"v2 gFƓd֌%n%\%_O!T"cOsr!OA 2nWXjnoG xKm@޶-dX{Y[f<%{,v5#icmƦmpwml6 };oo$\ڼP*gȡg3Fs͏ZuksmՐ[ e!p@dy?SYlŪx}[o{3:q_O"Zqkm?Ūf[vn1d1)$K$** M0b</ݔvwaG 2~>͈N 67PW7uob٬vP{ؾx݁7$W w'{wg|~f [7z_n?<8 7%{SfXӥuD 2vTz]WkxZ^Y _<~@d7iV&6Rur}?[˿HOE 2Y~o=\%c݇B D~h{C'jũ(ԕŭ ;n#PxvgPH[򿐲y3\7$׺;ٔm]!p;7qK8S须WԽڍ[yz;w3Rd7f,i_y%}z'/)&K,$/ x}bb!pB 2x={?@}3N`> 7 81C%3F~D}2^@vc/켘~1b!OG 2t.Aw%]x<*>yz|(mŖƑtw%+4-@@d “ YbOW]+_]%GC @d, JȲwgE 2YhC B7sh!E 2YhC BD̡N@|g; 7#{3f8!!Y"c6B ތ@d@g}3x37sh!E 2YhC BD̡N@|g; 7#{3f8!!Y"c6B ތ@d@g}3x37sh!E 2YhC BD̡N@|}x3ڗ#oX?o5zO1C ^C B ~@dW0!5B BWD~c ^C`+hB !Vʆ@@<ؓ9$@@\C 2v x2'sH @~5R-(ȯ$ڽUW^붫߭EݠfnsfTtG I,@Jovwcj7B1ac7n%tT W%{Uy(Ȕli87c{~ j_,a"cw poC~[wOugǴs:wi AP)WvanaawwkAn͍s&~7#J~Nl-A&7@d :o7$]"p;V띳2m J#O[cj< ?LGȡGM"3S3cG4G}f!p@dy~k5~Eg][1YV?5b&~gƟ#0D 2 т kgӪ~o~}!؇9E~8lƎn4aS혎N_i%ސ@^xCא.xVV1Ŗ۫Ucؾ~b'U{EvF[-i _웚Q_ߝ4)N 2F~]#Qݻ 0.dg[{٨Mz hdԏןDa#S=d_/?mȘR<$c~@|~߆{T:?XF&}y~qC˘Mg.|  cݹ4$a=%á[&A_@AXN+jqZtJLe~!Ţ~Ah2֜ I^&Y.aHQHѫj_Eze*kOǮ cvmoyz~|`Hq.@t3Ŭ rŁUH>;v5C!!^U̪z$Uyb# :3֧ XOZ!뾭y c]vs@ƺa.h0DMX3e(DX}!3c:8vfaAŌ9&A @: R^j#Wc:?ء1  Kk/$"5[/T k܁ow 3"E~GX]t A-@Z6?nf̫ %uxw6{fs!/@v}a :h3c2A>cuq 2[ -X4eLq,9A '@4U/CeK欎i.]lgXW#:]Vlʐ-\SBqX̛{=kV7 )sGS 2Q߸{)UZlJEeph q%5w͞Ǎl0QKgƆ^Q|'Cn7XKcbKdgv[|:'@@ZƊco;tl䘴n!Id.Ȟco3A<kNl"mWjVSNlň[AB؅uh?6c:kƞܳcq-TOEe bv` c򗧻'uPEQFӆ&ҳef}:ؘZ8@vHy:(t~lh1oFF wRyɘY )^7&MĎ34^$c!BFX^Yڦ(KYQ`+*I>h2֬릆cۦDtq?^!3L |8X.1 R91tkL@!dT͇_JyCG5wV c#=^~ w efN !pd:{9T`l+6y͌5B UUت:dfh,Ň.z֙1khUM c'@>˱e )J)]ȾƵ!P'dN*'6[dLU! `=׌.ca;5ޡi>@#,Sf%Rj#4CF2@`XۮM趍zM4[η \4Jkqay>*.jCz,'-gVqџ2ys?xUɊ&MYHq?Kq-ڸjnc@cyB[25G1ȝ% _όi#L!2 ['C;-VѨ+!Fa2H+sO\KY{e?7ԟ {?o@K cKhUu Dی`8rU@<ySRf^i)dҒh+v$KMpR, Й1P 3c$ۇ q-C. cQk˂_]*5v)\_3̌5ڗi6@ƶl ,R^QYd>h6=1ͲרTf#l#jl'mgxX"e Zc z!@:qXX侎̎WHkжf_Cv1u{2m ~,;UPufLS54@NCgf;@k<&M ?蓃w4{@"yu$k˼ywN!3cXM82v ]o׌ōZvxK)B_37 } c/V c9LC[FԚk VjO @`TXk3c26J0%C Hz4MQ:tŁ?_R`:!cu0nZJ\T0ͅ}y~XoU{$j23V{h#z;Ib3bl) ߠeY:@~n/ą7i, AkXaߚ=E !p4dh{^?xyvf!5uɸ?x<'dCxNkH0f0GWӎ5Cx Nk<^u)f+6=gP펗 B1X3y >ϫ)_ÓhPG;W[>~ s;w1.& cM灴×flK;!p d@{^ZfĬ&쮥iCd亰Н! ct/ p(.ny482v =/-h!cq_\ @]!H >>3&čHKCXGɚhAhTUh2ք,tO;dͳn҄h$ p0d`\~Zɼ"iӎ؍2.W>|V^uL@@ƪȶX,L U#c^XH\-@ƪC”3cw[ c^{33c1!ëDckA7X[>ڛ{l4!c83W@Kڽc5ڛ{ldͳLy{>2Vw?,E{b u79]4fي|  c8'o-|G~ϵ1si4Fhn=bbݍ=u.cy8hn cU{+"UۛEB:>2Vs7v6`>C@ Xn$pJdkiN& |퐱zT(r0 5dbJF`ˤl1]4M;xŠgv3dmjQӟt1{Mw\sy/[X3Fܨb.}1TlIXJ;ؙ]h9؍2=/ld,I4g"c~^% $G.iB@CQRL54ŅyiMd6 >~127oN]qt1R ^e4C0KXpWkzKr&6:W4Yea );:)>[񜝎w c?xT dwsSIL^d,?}[Bd>?K晘q&[> nǹ2VWM Ÿ$|ǐM8@*s.% .:κ8 =fR2VK^2~$Y9q7`AOaGvevmi/<Vm'B@ i bXuB&ꭴU@ƪpClëTZ|twQ1Y dN6$K1G٫4@B_/p㿛퐛؟2YXOqK@[Z0|oȓچnq|~CODcRfh2WWX k.VK*L҉oV)dχ$ crKq1\@ƪwH=cSL1X޿WsytCF̘|K&l_cP͂瑶hez╍ewTbhUc8ee{ l\U,Z1[sC46[+ 0OQ\#s HYxiqj*N)Rm >=_?X>q,hLLZa6%퐹}D 3]Gv;@9eL)䓧[Pdіfƙd邰tf՘?4+G ƶucYC6I,TdݯܣU&SIՔëO?O;q&0; BƊʁ؏2s]A&'9(~ +&^,d,@Cs)/c7r|PqvV}?0Fc+>ĚQ_b9KqX٠\K -cK@xl^8~)\|%,hOscmepmoW*'] )Ak<6Â!ӗOkoc)!`ʹ+=Ue&6@@g>cX*v&cٜ,#Iw\kʻgnl%?NkFˎx[bTƶ@\tN6 ?-]jMyd*V* cW!T _٘i!ţF&TB7kuFfDcVeucr&z'][w+[{4T\D{^V#X#~oј`i2 p d-+CXTgm~ní^U_!n\KU,d2Tv t37d6ߞ @ @Ʈc/;BLS Ӆ2f:j~h" 2v}{\&c'4ڢ1Og'4[@@Ʈ10lGK6Ӟ]24DTP/iwzd7Mfe)$e^ ik19v!˶ܽ;R$2n%0ݵџ%,zH$_{*F$O|gJ;\ȡn([M/)RvϾQ'f)fǢR7L>@W [q+T8r;wCE1dL=w!Ho*U?z  [fyj>Ș_i,{/3zQX="2C2&#UO@, ILYL#w~M<[EvEC98-ٜ3wi0:=ф]Ӡjqsؙ>X^3ͳi,iZI)~ɂـOCr=rRAƲ m/1{Sz? ns!<ŬN  Э0S X6fO0fB5}=ݝQj֌]dlR-ׂCe,V_jfZCi ~/I1+~9#Xby^b :7_WHgs/2_}I̍9D˘-[sf뽸II+[;TGxa#VXBހegjTʾ cOly~o!ba$O` ?POMl;B*c͍:T vyl3N|8Of)],|_w"@ ,c!^bxJDdE|'_%u5ҕή^Ŧ2[Ot`i{^m$qr]6hzp&0i _w1}Mr9\)Vc 7n⫞g'?RTZ{V*vl2(+̣yF4(he F1n WFcoCC$5cvbm]> J`hCĒU5/F@q7vel2.S1:|/{Lmr6 2sdŘO{)'hz )/LxB&NS,Q٠^26t JJpN':;;ˣ?ϗ,t}\ҡS6cvy'>!<μK<>{U r)>rCsq]N aY:?6 A׎; XayMkDe!&dDHIX@J\dEE;aێgYwӝs|؁ ˥!p(dPesui F2++RK cKhm9V 7%+lwj=*[9Hln82vٕcz掟tNnci@x&'lݳ>%8v{NkUU)'[AW@Ρ~ ιdkOBi+P@E)^G':Ko}ϊu+ ^z ?|ʱ MT@BNm8RTKi3=4=nyԹ!XC}儆|ż:?ê+C'bV2vcdUTlW(cdzh, ݑrAM;xOMn ㉚(?5<w_KAמj7K0*/BKm>^Geuv]ږ:we\L[pi^f{z|7mCZ1h؇WBdbX0vg3&-"guFK[,.sx,3w ~&eqO@ bս4;_yNKӵc(3 Zw*S|z퇗+Ai M:FU Ƃ?3s|f'{]d,RL"Q{9 PdlCP^wϩT-c&=R~h,ˊmM!oeuTGp3@`dltpY@&cvgU)+pBIy#N+̓2dD`zпU{~گPYq-|+Aŕ-4@\j?2ɫ$E %nѶ%d1R- ,8u%4M3^YD=g;ml J[:G%;)35[QԿ/G<#fAZaGwH@:߄܇s>#Ϧ|2,I3ct8D::VԞO֤d+%(if BЖBuM dl?ezz]+$m :[wԌOv<8@nzi^&"Xىw@@K,  #momnJPV{>}s@1Ӷuϟ!}8mg+Z:'W@pS@A^VshרNc9n.6 c-T[,lp J@=W@~ c;y91RFmF[K %תɟU.Ag@с؂0a|J1XqJygq9 Io*1 KWAw=!dlG/Jl`#~MZߣ] 6 c;)>-u"zmlEA+Xf.TErہՙoJY:c;\ @vrغgR@ĎpK 0[Uz. TB6e*V5{mNݏ@``>ηJiDgbZ~ CnU,W?y&̉h2lې8k< >1"E:ag  P#dl:)˦iȪͷ.KFr͏\2\OU_4cbv6^!ȗ~CuW@ ^5L/# YgPN|ޱ{sTO"y6ec\kUǪηO'S!'zP~k|@%LlKfzx--CΞJ!/ޖ_gck5A9:j[ߗeUCB@"y$dzۜ cbgEvtM3ߢvxצE @vMpgk4F9yY:*f$/ V c+<'="m/;x#YCv?}!VS f c]J!*vz^v6'Wl^$-t"zrV(P|E ٲ҅;<L˼?V\2 XFekGбw{9}He.o;ٲh2e<7MUcG7쎐[eZ"-e(8晗ʣݏ6Yi+ . \H[yŕa|J/  c\><?Y-}͇T| p"dI{?%n+X2Nղd+^+E+U6be5H@Q, {R~tU>u:Q lO^R뱍t9؏2VҴ+ۼˮasݺsw6hyfeFs؃, }lQ @` dޟT~j, #8c#dLg=n( c=&RykI:rBZ,;f8ɘjֳ=b| Vo6-f.p$Q/yO3Ƴx7*&4-'ȼlows d쇿ȔEVca TQ`P\~\*<<7ǺCe盲6V{X ^T Zs]bUY(TnU0!e4{@ƾ40ՐLJrG3ER9:X ?&{ƢxŽ~G 2 _C/ﺆ6mx&]#LEY3=S2f>Ci_'k2lGd1kˋxoꚨοTzIrEaDv\@>9fD,ޫjGx*^0x]7&>\i%~kkz6 p&dm}× }or?}0WǑgc_2 ǎ+^1e&<5TƵ{X<@v Y1rA(/\k5׌ekqVL5`DqielgV綦tq_js8HNp{ -w\w ,s?.\Y3)Wiul]o?5tPׄ߶:t4fq  2Bs;|.%latυ*\OWuHO i!/_gł5xU]co5Of1*ek<92iųJ1x⇮ⱊf*!E#pe1}U*f.νIѯxv(@asdQw)*faC c9.w/qeiC[E?uЋ %aU5)|>>wȑkt,{1,v @U?K谹]eҕ Q2(2\ǎH"QчX6e[&oqc҅R RkzW82Pb￬̸+ 阥%׶h,7/? ~)%$|bX9+dXd;22-s:TGxkHlؖ-W_oϗ)>2$*I0[_#vfl)c,O1}DB݇kB c Q+&l?g*V4(a|TTsR?T/-C+6wۯŇ!cx¸Zul#2ffr}YG2[齬D>ɳ鼲6Ty)K~gi۰=]#([ Jʅe)CW/X?]V@S̟gVMg*!cs%1;•gMnke|/2_K¢szYƒ&SbשEA)ח=r2f6i6['y{Cb,<`jdS2 C$6Ef2h/MAiԇgh;b w%Ѡ_#T/9|GN`LUL1M(o!]:+VV^ }@t$ 鷘CDz8aZ.g%4)n RZdmS5+:_͒M'Y[>o^v]C!e-5O/^6ቻ^||Þ~l%tAtW>*nF |3.^gSܑb;dgX,fCî9:F._dwiYs,c^ ƩdqY:fqCܟ$)$/Ƕ@(ЪGPED!ŏY]:ũsS! "AwzMs`U>$73=<\2;6A`X s*RfDs Ud%#c]F\ﶚjrscvi86I%fh#13!ws iz8.[so΁VY*,bP<9+z~>]Xr~ℐJ~DBEҠb105;;|l\N_J^&߆3 *cqmGCΞ^=~J#='T'_>WlsNӺS,jh߷QfS\idq" 1e_Q_E@ۘ[>gO\MsB߼;\3XUͧ*U;\K@GH|c:⳯,dۈsvBPu+f:FHVaGI}dAThOi6-gܥ\GlxGh憞Gc*ZRU z֢kJ_,*ٛhm~i{ *Z/5)tG /1KQ"}>̍-K,^4z׷M||`f^$qseGcVJz/qsf +@`AdB1{@Y}(˃%SQwZyydAƤ ?W}REeTyu|̵)^sq\Q^P .hCUmE\ؗ2˺18qԂh*7~$ȥZdvjߞWˣ1/SWUC%~ħƂ|tk5Cش*v׷%ʫxZĺd yWI4B1KīY98a[vFc^Rb:2-_隲#1iXG%oqܳ2N#0]>AEhq o. rG)f1L>Wf!Wڻ)S<[`k!OscyFf{>ƨ$,rZB<[c!q$ 2Onr)k* l@&e)[Y:I8wq!AvW|SG%T~7&e+T4a1Sqj^zbqG{ {_!-XaIh(|+y4'$eW2o> 7>X&tmqtGg8`Vd/{sob8cJpqٯ7g]ش$6-W%a9uz$ي/)[?YoABDfE{]yF@(A$z1- "N9 aOhʊEu͏y )8@21{$E&[( cTX]xOE~:@~o<䵂I)Z:oǧ ˪kvgy/:eLXcwMyBoO\ JgKSFo fl%irFŠ]WKeZCa'C>|LrgqR;0(mgibNGGdb42W_B#QrX ӯ u嘕8JSPJ^D ̛tҕKd40M|xu{ۇEWɲm8[W& \ =bD^Ӕ;ZCc`j. t+cSB}v1UTAɢ>6gI z| Uy*T\chj9f`9h VM1Dc A3U 0;$NٯYT;wSe׬4{?F+ևOjcHSdZP4[WpCa ʓADlNABq銦Z5,_?ck9z4O'l/i20_= ]Q 4kٽ|ћ|jtFpWh,ݡ}]ʃOx/iQ7B}ʘ f|*>?Vy{'M)7®YӢ]$kJ /<;L#9ezy%E1U-6S]E 6@ ČW|$/n;B[]X|-ۇu!Ύzʤk/y}a0&{+߃وh|TQT*bn!fSb|F}f̥$d 6j4z͸4 PDK!)=hm<Ȃ0iX1kL J qBE:V:N\PlK%[d0}hy<'uQtV\1N @PʘU5/jR, =H:xZn1hnG♱X]>U Ǐ J9.dRޢ8g(]S2^؋ջVS dLU@wZy'uָƽLbX\9*843rNDhOuUdgQ0}#bi-lC`TX,`bFy+*?*ܺHxh{ ^G䈑Y[j.(>!>`\NRW>ũSx "uԥiȚc٨|\Ccp~zk9*;jPY_i#Л'PQ R>=6OW|x۟2EkYW QhJ*l쩮}mZ1(۽qo.۞qLA{@+dL,&*5uƢB3?>c1F(wT.Q~Fm/66KqT!8 tN]! VK~j.DoTeomrJY"FSa濽T!R x*Vc3KQ#)c&j_f~8QKƢ*ԗ1UP4Mt[_qD/o3W.Hӊ:sa9֠qϜ7SzaT8W!=1"!д+:+~KU{˞^ct|t )j0Ofse;jc µۜw1V׶Yh@O2Nʻ,mr#uGQU9sba\c ZݎT _T7"SРnhcaZLULw":FMk1RoyHy#ciS^؃>hM= GT'ѱ/!E֪Jio2_713=2 +j,(?v\-;U nV @1ݯjP1IK=xubRȦJu|@1bz:M[{eLB7nG3cew~zQiYdf |u{>9/ 'Ѕia7W'ӱ)QtU7Y5LrEtFa=LI1+s7bnշqVM3gk|a>i!){u .dL'D*j6>yW((PX>7#V)e}LGa/eE:'ܘ 癛ID-#مXscpkIň c?Ԧ>Tb+{l'^q;[=K`eRgu ֜0b.Feb֑P% t clU/Y{C11â/O4C&m ItF}vOfTle:G(ZWZ2uŘ~f<ӱJrdB p6eL:D5P݂‡R[vʨn,~Llh+WUظzalYDg-j1?׈: ܷI\ ch^$% %9iGﯬ[ќg!c[Ia#gѲj׍8 ]~LAs9h]tŘ>u̇}b0kMQ։,<'j~{2!Kkjڷ+BII"3:buP>c;:n9h\Ƭ.kXSyZ#c%ZKy% Xvǫ łXAĞ~l-;M.xSG;Pm^".cAchY#>b5e6Y,gSi8HgtTD: 4,caF D 4*c6*Sg3s'a~vW~chP|!e]賳A_v[0MW懑_9 @{2&;Õ/ޓ.0b5h:L-'=nmʘ=\9XglWI-*y}f|Ӻw1MD#&]\s>pЀO9K3c)14S L.,w"cM.mA` ɘZe+%ctb+Y0o QÁXM58b6yaP d/pwk:SZ1_|ebC^9[e^k_qɘo[>_$#Zџݏ*y#o@[2 /WѥbWa?cԹ`iڒ~L;=݈e2S+S<4%cM_E؇WynaZ  4%c^^s1Pau:h5j h{ 00d 4f꽖غ:_6Y؃Te!hJ$w@2)y<>? v`yRgyߙm$c2"/>{~;_eƚ.ڟƣ5]s PN-XHro4\k $xU~cߺ—K8@{2vYN>!dudYI|  #cy<\:, % C>ofv a 8vdLUL+#Hk@]jw7#k 4#cv5bE&Zo#JO5e_\ 4#cVv}fP.Jw٨b#M޵6n ]r1<hMH4D?*3c}iv &cT` 9>76|EcnpK"Ќ$cO'eCLySEUC1Ym{g|fIǢ%~D|<\duT͐N>ņ 4)Ixp hETŴ2/Q!Q,Zm;ig;hly hEthF4!>/AI@0Y< &3?; @`=dLW>N v;#(q<>CJ?#;u̦:O+Q-""c:诶ǽ֧I2tq+Ȓ'RwiOɾ;Kڱa@GhEBq^D)'spDRωɟ8h)'GPʱK@@#2r4㈇VK#aRL&sm|R#Oh&~}&:Vmxs P6d*~Ya4ٯ{ d)^u^k4E5J[GgAZq. cnHz!ІUcDcb<*ZݎgSW;trvjoQYMX>M,2ByƧ꾧it-8Dɱӥ' wg鐉O]K  ˇLSYhNx{ʔY)~󎺆(`c;e*U#&dC,Е/l ?uqo1cNMaXml 8kuԘqu8SMQ̞n2Y_+L"طHg)4+Jo'_BT1}G pE/߳uZ)U5YFQ|k6$Y zf>S%VBQIN46C&peBU$c>o"ɵcQU,Wt?cORk:Ƽg~Q(cYFMտAB -@e2frm> CTS55_X#[yȞwZ^y7fh/)iMl쌷텿VjfI69jiKw>pT$;92O2Wl1޾-#Rxe2f5EDX'ҪfBRelO6I}u¾/! cJSȁHǢû7@2VksnO\-Yd!#G] 1`hf CVm@)i@Jm+`evٞXK QȾYԭZ"N棊EwS1{I|N %ɽYsa7'}A9s׋_r?\ps>w]kF И:DAa]yeO#Xm-k:ʘce!0y$o&ܱ #7@@ D s<4syExt|,<蓞qٛHˮ1[Q9K2j6zw2vl tQ B+0$aƧFiS` FP5>V},Kʂ6on{M֧8lꑱc.0CC"ib|KdGi`iMKٓG:kaݢ0yxbrh/0[ByX>*rx<}8=M|q+.~8..5mߟwMͯ'rv7(yr ]L柌Zdlɨb\c+t€?g/\ž`ȑrz8~j-[p!P-J z!;M7q˯iͪ}XYb=) %d=0e}~  P-H,O1De2w|G2 C=<ޫ}N@c >?ɸqL? sD҈6>JɱŮ -+f)ꑏyڟMN[KYe!2ئaOW:kG?U| rs-e췓 Șx,W/[uaN:ŕ! T%cfxfpb!*+6[sݣണr]TM"QJʂƯڣ6NF X>.dH+q;U\Cs :dŃVu~61zxK`f dUnl!PՑaiդopJ= $cuScf ?&oӺ]& ou'3x{ T%c5aЙ1Ҷ/n\CfgC T%cW et4XO6zTQXߟ.>Qŋ!pd\Ň(] %{:h@]2&WYzYזr߲h;VN.U2Q\Տj9!ZBO5㖖ؘY=vq#@@Xi46e/\Y&bHg:힯^ؑ/M!LƊߣE\ߦd1O3[ån9fy58^g;b&NC͍ p=KdOCY<$wQzuqؓfG[P6T[i %2v%2&3-~t!=1)[ Nq3IycFfw=!"ЃUd2Vn}>ٮ;j>m*F#P-^{Z5^?Pf& l!P΍7]3|[s. @V[@%k87 %2&XT)̊P@\ع&vQc7.N$@3XCqܪKMi$ ڤl}@X ceΖL6%ݐ*5kg1T 1j]>8 $_P4$I82VF7T@p},Y$iYGֲ\ɎvׇaBcu)4ò̎mLR~/# A+dy⹐Yiah1 fb=_cgy@`oX)kޘ L%i$U&cϲ *dU 2fDzU))Cp60]L@k3@}P~f @@ 0dat@@ 0dat@@ 0dat@Pp* CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5B2֡S1 8q|:$uTL 0dl_c)  c: CX @CXN$@@5Bzz tIENDB`[Dd <r  !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~8 7Root Entry  F EU Data +6WordDocument .TObjectPoolEU  EU _1225221918!FEU EU Ole PRINTCompObjb  !FMicrosoft Excel ChartBiff8Excel.Chart.89q Oh+'0HP`p DELLfPrivateMicrosoft Excel@LjB*@& @5  <   !"#$%&'()*+,-./0123456=9:;?@ABCDERGHIJKLMNOPQ>STUVWXYZ[\]`abcdefghijklmnopqrstuvwxyz{|}~Y5%  :   xM''  Times New Roman-Times New Roman--Times New Roman----------"System-'- xM "-- h< "---'--- xM[   -   JJ   vv //   [[  --  ----jj-BB----'--- g<---'--- +%Q---'--- (%Q0- "- %u 0AR2aMo% Moh| %% %@[v"% '4uBiO]jC*%  'B]x "-uuk "- "-oMDMDCDX "- "-%}%}}0 "- "-ZZZ  "- "- "- "-u- "-$uuku---'--- (%QoM $MeWoMyCoMe---'--- (%Q% $%/%%---'--- (%Q $---'--- (%Q $---'--- (%Q $---'--- (%Qu- "-  k---'---  (%QoM yWeC---'---  (%Q% /---'---  (%Q ---'---  (%Q ---'---  (%Q ---'---  (%Q---'---  +%Q---'---  xM---'---  xM----'---  xM  2 0 2 10 2 |20 2 530 2 40 2 50 2 a60 2 70 2 80 2 90 2 F100---'---  xM----'---  xM  2 Ji2 2 JA4 2 J6 2 J8 2 J10 2 J12---'---  xM--------'---  D5vc 2 L:2 h"vrijeme nakon injiciranja (tjedni)        .2 time posttreatment (weeks)      2 L----'---  xM--------'---   Times New Roman-&2 >% smanjenja teine simptoma (GAS) -Times New Roman-2 Ipercentage of decrease of the -Times New Roman-!2 x4Patient Global Assesment Scale -Times New Roman-2 -----'---  xM---'---  xM "- 0-  h<- - -4- "- 4i >--- -  - -/]IArial- -   2 I*' xM--- - t>H --- -  - -o2L- -   2 M*' xM--- - _%3--- -  - -Z7- -   2 8*' xM-- -' xM '  'ObjInfo Workbook VSummaryInformation( DocumentSummaryInformation88 A@\pPrivate Ba=   =$<X@"1Arial1Arial1Arial1Arial1Arial1sArial1iArial1iArial1_Arial1Arial1Arial1Arial1.Times New Roman1.Times New Roman1Arial1.Times New Roman1Arial1Arial1.Times New Roman1Arial1.Times New Roman#,##0\ "kn";\-#,##0\ "kn"##,##0\ "kn";[Red]\-#,##0\ "kn"$#,##0.00\ "kn";\-#,##0.00\ "kn")$#,##0.00\ "kn";[Red]\-#,##0.00\ "kn">*9_-* #,##0\ "kn"_-;\-* #,##0\ "kn"_-;_-* "-"\ "kn"_-;_-@_->)9_-* #,##0\ _k_n_-;\-* #,##0\ _k_n_-;_-* "-"\ _k_n_-;_-@_-F,A_-* #,##0.00\ "kn"_-;\-* #,##0.00\ "kn"_-;_-* "-"??\ "kn"_-;_-@_-F+A_-* #,##0.00\ _k_n_-;\-* #,##0.00\ _k_n_-;_-* "-"??\ _k_n_-;_-@_-[$-41A]d\.\ mmmm\ yyyy                + ) , *  ` Chart3"Chart9.Sheet1MSheet2NSheet3""l3 A@@    A@MHP LaserJet 5L PCL@g ,, @MSUD7HP LaserJet 5L PCL%d " d,,??3` /` /` 0*` 0*,` h(  hr h 0l A@]l8m <*<rr h 0l A@b]lm <*<rr h 0@l A@ S ]@lm <*<3d23 M NM4 3Q ;   2 80Q ; Q ;Q3_  NM ]  d4E4 3Q ;  4Q ; Q ;Q3_  NM  d4E4 3Q ;  6Q ; Q ;Q3_  NM  d4E4 3Q ;  8Q ; Q ;Q3_  NM  d4E4 3Q ;  10Q ; Q ;Q3_  NM  d4E4 3Q ; 12Q ;Q ;Q3_  NM  d4E4 3Q ; 12Q ;Q ;Q3_  NM  d4E4 3QQQQ3_ O NM  d4J[@4 3QQQQ3_ O NM  d4J[@4 3QQQQ 3_ O NM  d4J["@4 3QQQQ 3_ O NM  d4J["@4 3QQQQ 3_ O NM  d4J[$@4 3QQQQ 3_ O NM  d4J[ @4D$% M 3O&Q4$% M 3O&Q4FAx 3O  3 b#M& 43*#M&4% ? M 3O"F&Q ? vrijeme nakon injiciranja (tjedni) time posttreatment (weeks) '4% MZ3OV&Q ,% smanjenja te~ine simptoma (GAS) percentage of decrease of the Patient Global Assesment Scale '43" 444 e@@@@@@@@@@@@@@@@@@@@@ @ @ @ @ @ @ @$@$@$@$@$@$@$@(@(@(@(@(@(@(@eT@T@N@N@I@I@K@K@S@S@@T@@T@e>   A@"T@m??t3` 8t"` 8t"` 8t"` 8t"` 8t" ` 8t"  ((  (r ( 0l A@ _o ]lm  < p<0.05 N=21< L rr ( 0l A@]l m <*< rr ( 0Tl A@) ]Tl m <*< rr ( 0l A@ hS @ ]l( m <*< rr ( 0l A@  ]l m  3dE 3QQ ;Q ;Q3_ NM ]  d4E4D$% M 3O&Q4$% M 3O&Q4FA{4 3O 3*(@#M43*4@#M4% t|$M3O|&Q ~=Time Posttreatment (weeks) Vrijeme nakon injiciranja (tjedni)'4%  MZ3OU&Q H"Percentage of Patients % bolesnika'43d" 3_ M NM ] MM<444% jOM3O$&Q BPATIENT'S GLOBAL ASSESSMENT SCALE KVANTITATIVNA PROCJENA BOLESNIKA'44e@@@ @$@(@eT@N@I@K@S@@T@e>  A@  dMbP?_*+%MHP LaserJet 5L PCL@g ,, @MSUD7HP LaserJet 5L PCL%d " d,,??U     ~ T@$N@I@K@S@@T@~ @$@@ @$@(@ *@@@ @$@(@6 @T@T@N@I@K@S@@T@~ @ ~ T@ ~ @ ~ N@ ~  @ ~ I@ ~ $@ ~ K@ ~ (@~ S@~ @T@ JJ<::<<<:0 (  j   0NMM? ] `H m  A@MHP LaserJet 5L PCL@g , @MSUD7HP LaserJet 5L PCL%d " d,??3` / ` / ` 0*` 0*,` q@0(  0r 0 0,l A@J],lm <*<rr 0 0H-l A@t]H-lXm <*<rr 0 0-l A@ Y ]-lm <*<@A3dl23 M NM4 3Q ;   2 80Q ; Q ;Q3_  NM ]  d4E4 3Q ;  4Q ; Q ;Q3_  NM  d4E4 3Q ;  6Q ; Q ;Q3_  NM  d4E4 3Q ;  8Q ; Q ;Q3_  NM  d4E4 3Q ;  10Q ; Q ;Q3_  NM  d4E4 3Q ; 12Q ;Q ;Q3_  NM  d4E4 3Q ; 12Q ;Q ;Q3_  NM  d4E4 3QQQQ3_ O NM  d4J[@4 3QQQQ3_ O NM  d4J[@4 3QQQQ 3_ O NM  d4J["@4 3QQQQ 3_ O NM  d4J["@4 3QQQQ 3_ O NM  d4J[$@4 3QQQQ 3_ O NM  d4J[ @4D$% M 3O& Q4$% M 3O& Q4FA2 3Oe 3 b#M& 43*#M&4% n 0M 3O"J&Q ? vrijeme nakon injiciranja (tjedni) time posttreatment (weeks) '4% hMZ3O9&Q R'% bolesnika percentage of patients (%) '43" 444 eee   >@  7 A@  dMbP?_*+%" ??pU>@7 A@  dMbP?_*+%"??pU>@7 ee   >@  7   dMbP?_*+%" ??pU>@7   dMbP?_*+%"??pU>@7  ՜.+,0 PXd lt| MEF Sheet1Sheet2Sheet3Chart3Chart9  WorksheetsChartsOh+'0   <H d p | J  C A? "2ɛ>sI\a7 `!ɛ>sI\a|nJ 25_xY]lU>gfv[~ h1Z14H #DcPFܥ--ABOʋ/$OF^L"`L>_ O ܟ9;?e[wms7w=߽3wfrQÓ`d,y6АWf) $5CjRxA_Fr="tZ–hp[J@jhGo"iDFc^D"24Qu,ĭ%2c5)I`Iƒ]`c7}quhZd|.*Ƃ{3Yn~UhU ՘^k¿p]֯x2[wb,bqD'JGS ,2C0=p8!%kB p;k).,ţ@BFq88 i|68/ \1ٷI8<#:r$C8"ay6wb$ 1veHݥI1vSƕ޽Z clSzSZckkhkһLK11vD%)K#*c?a`Wb1Fb}VѢX_ %T==#֋Wca?8*!l7+Q㕼2h~ 1FU\`C%xzP8B8(ۍJW'h}E Ĥu*y5G9%έx30+M{s\k=18N,N$J#y!ΦScңo帩8B<@lب@L\C,lXK[EoYӰS][yͷh^Y"B7[tNƞa5>lPcK}+{Ƈ2֮g%6SbmY!d;2our/;6 r:O%CJdYYFHF&:V.ͪw1U8<wk ~Y2"q|xX.[OezؓN$~N9Rv"L&N*m٤3X,<0;p!:' UlkBCdKJOHw0,edi6캻3]JDڱ J}ꡢ۠w:J uZM]-5 FLZ!v8 ]NDʵ3,dŻ7/'-Uz̥ ^*gkat{`2Rξ#FF'ݙչsh++\?v:ҦMNQ ^Ft`;F0\r ߙg< r9ȋJe#We"$1DᓢS)3^SWԮūtNW >+ uCh_1CV fL*3Us;¤הO{ I$M=[wbثYNY's/S /1Table_fSummaryInformation( DocumentSummaryInformation8F>CompObjk0Botulinum toksina tipa A i kolinergiki sustavPrivate Normal.dotZdravko Lackovi13Microsoft Word 10.0@@ @@?$U #T  FDokument Microsoft Worda MSWordDocWord.Document.89q  PCtrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15947626&query_hl=22Oorhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11742168&query_hl=47Klbhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22King+DW%22%5BAuthor%5D[iehttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Kennedy+ML%22%5BAuthor%5DLffhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Thornton+MJ%22%5BAuthor%5D Dcrhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15820455&query_hl=13a%`chttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Spicak+J%22%5BAuthor%5Do:]`http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Hep+A%22%5BAuthor%5DJZbhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Bures+J%22%5BAuthor%5DCWehttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Plottova+Z%22%5BAuthor%5Da4Tchttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Siroky+M%22%5BAuthor%5D MQehttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Martinek+J%22%5BAuthor%5DNNrhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14710908&query_hl=12[4K5javascript:AL_get(this, 'jour', 'Br J Ophthalmol.');GHahttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Jost+W%22%5BAuthor%5Dh:Edhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Naumann+M%22%5BAuthor%5D~ Bdhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubme՜.+,D՜.+,\ hp|  PCyZ /Botulinum toksina tipa A i kolinergiki sustav Naslov< 8@ _PID_HLINKSAd<nv?Shttp://www.ingentaconnect.com/content/libra/cmro;jsessionid=qai1ez9umxpo.henriettaLrhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15377314&query_hl=11*vdhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Pogoda+JM%22%5BAuthor%5D+chhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Schoenrock+LD%22%5BAuthor%5Dw!dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Blitzer+A%22%5BAuthor%5DPbhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Brin+MF%22%5BAuthor%5DHehttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Sherman+AK%22%5BAuthor%5D2vdhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Conway+RR%22%5BAuthor%5D/zchttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Gnatz+SM%22%5BAuthor%5D1vdhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Wilson+DJ%22%5BAuthor%5D^fhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Childers+MK%22%5BAuthor%5DFbhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Lang+AM%22%5BAuthor%5D&oqhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=2300249&query_hl=15i:chttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Nikzad+M%22%5BAuthor%5Dd5ghttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Ghazizadeh+S%22%5BAuthor%5DV>-javascript:AL_get(this, 'jour', 'Urology.');N)~http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Chancellor+MB%22%5BAuthor%5Dm|http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Yoshimura+N%22%5BAuthor%5D_9~yhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Huang+CC%22%5BAuthor%5Ds2{dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Stohrer+M%22%5BAuthor%5Dy1xchttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Kramer+G%22%5BAuthor%5D}%uchttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Grosse+J%22%5BAuthor%5D Frrhttp://www.ncbi.nlm.nih.gov/end&cmd=Search&term=%22Thoumie+P%22%5BAuthor%5Dp7?dhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Lamotte+D%22%5BAuthor%5D} <chttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Wallen+M%22%5BAuthor%5DM9bhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Hoare+B%22%5BAuthor%5Dz;6chttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Wasiak+J%22%5BAuthor%5D F3rhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10517680&query_hl=40h 0ghttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Carruthers+J%22%5BAuthor%5Di+-chttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Borges+A%22%5BAuthor%5DL*mhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Espirito%2DSanto+C%22%5BAuthor%5DX'bhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Costa+J%22%5BAuthor%5D"`$qhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=3561773&query_hl=12e!4javascript:AL_get(this, 'jour', 'Colorectal Dis.');"|ghttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Mortensen+NJ%22%5BAuthor%5DFehttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Brading+AF%22%5BAuthor%5D$xchttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Moore+JA%22%5BAuthor%5D?mchttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Jones+OM%22%5BAuthor%5D4nchttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Dolly+JO%22%5BAuthor%5DLbhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Aoki+KR%22%5BAuthor%5DG bhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Molgo+J%22%5BAuthor%5DW ehttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Meunier+FA%22%5BAuthor%5Dehttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22de+Paiva+A%22%5BAuthor%5DWehttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Stevens+RC%22%5BAuthor%5D]bhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Lacy+DB%22%5BAuthor%5D@`@ NormalCJ_HaJmHsHtH \@\ Naslov 1dd@&[$\$5CJ0KH$\aJ0mHsHtHP@P Naslov 2$$d@&a$56CJ\aJH@H Naslov 3$d@& 5CJaJP@P Naslov 4$$d1$@&a$5CJ\aJ@@@ Naslov 5$d@&CJaJ>A@> Zadani font odlomkaZi@Z Obi na tablica :V 44 la .k@. Bez popisa R^@R Standard (Web)dd[$\$ mHsHtHRQ@R Tijelo teksta 3xCJaJmHsHtHNB@N Tijelo teksta$a$5CJ0\mHsH4U@!4 Hiperveza >*ph0W@10 Naglaaeno5\OA ti&OQ& linkbar`Ob` Naslov 221 H@&#5B*CJ\aJmHph333sHtH0X@q0 Istaknuto6]PP Tekst balon ia1CJOJQJ^JaJF'F Referenca komentaraCJaJBB Tekst komentaraCJaJFF Predmet komentara15\ZP@Z Tijelo teksta 2$da$CJ\aJmHsHHV@H SlijeenaHiperveza >*B* phNN BUTekst balon iaCJOJQJ^JaJT/^_8-l ?   | ?Y8GC!!!##G&')*0E0045L8h89<.ANAFGIKKgMPPR#TTXYZ[\]bcdh`kukrstwxx{{{ ||1}iHLԈ\ ΍F@"8"~?#ҝ7ͣsئ*h۪Cd89yq{Aj{? "<=>' 01M789dhiZ !V1 1#$=@n z '5CDYk} *+Kdes 3TUamny1MN\jkz/FXm!7Gis)Kjx*@d}.Jbnyz{~000000000000000000000000000000000000008000000000000000800000000000000000800.A0.A0.A0.A0.A0.A0.A0.A0.A0.A0.A0.A0.A0.AX0.A0.A0.A0.A0.A0.A00h0h0h0000w0wx0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0F0F0F0F0w0000000~0000ҝ0ҝ0ҝ0ҝ0ҝ0ҝ0ҝ0ҝ0ҝ0ҝ0000C0C0C0C0C0C0C0C0C0000y0000000j0j0j000000000"0"0"0"0"0"0"0"0"0"0"0"0"0"0"00000000000000000000000000000000000000000000000000000000000000000000000000000 000000000000 0000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000 0000000000(00z0z0z0z0z0z0z0z0z0z0z0z0z0z0z0z0z0z0z0z0z0z0z0z0z0z0z0z0z0z0z0z0z0z0z0z0z0z0z@00/d@00(@00(~(|9|***@00/0$6Trr:d,ITTaHkxF2{    %8`F̅$SwP$jlN "\ 0h"B>`|~  !"#$&'()}4}}}}~~-8;@HKDJUX Гߓ&%-0ޙ"ʛכCÜќ֝z)14؟ʢ͢r|!ƥХӥu|p̩ߪ_gru"%ˮ֮ٮ|(.1հްh'EPS@%s=BLʼͼXfѾ4ܿ}$03:DGS[^ oy %XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX: _Hlt150527703R77 _Hlt131862546 _Hlt132369061 _Hlt132369062 _Hlt132369063 _Hlt131862701 _Hlt131862614 _Hlt131862605 _Hlt131862569 _Hlt131862600 _Hlt150527405 _Hlt150527382 _Hlt150527383@@@@@@@@ @ @ @ @ @0s z      ( ) , 0 3 4 > Q Z [ c d g h o p r s           0 2 5 6 @ A C D H I P Q W X a c k q s x z { ~     $ % ' ( 1 2 8 9 D F J K T a h l t u z { ~     '(*+.7=?GHKLQR[\^_eiuv~  ")+./89;<@AIJLMSUZ[]^agijuvyz|#|)|-|5|:|A|\|g|i|r|t||||||||||||||||||||||||}}}}}}}}}~~~~~~~~~~~~~~~~~~~~ $%/ACFPQWY`eklrs}'(238<EFIlsxǀȀπ&.7KST\ainrv}؁݁ $).49=BNOVWYZ`aimwy|}‚Ȃ .078;QUY\`gvxy| #-6;NOSUXY^`fgn16AE $/9AJLTU[\^_ghpqx؈߈ %&-7@BMNPZcgpqwxzʼnɉΉ҉։׉݉#3<=CDPQW\abklpq|Ȋ̊ӊ׊݊ !#$*+/1459:@AI`chlpsŋɋ̋ҋڋۋ݋#,048;<BCEFKLUVXnqryzˌ̌Ќ (679:=HJ`cdtuwx|ҍ܍ (*-JPUZ_cnstz{}ǎ̎ЎԎ %&(>ABKLS[]^afklsty}Ǐˏӏ׏ݏޏ %*,/KR )*23;EPW_cfgnow}ѓۓܓߓ &*049GQTZgx|ʔӔԔ֔הڔ۔ Εѕҕٕڕ <@DLPZ[`bjkuzĖɖ͖ӖԖٖږߖ /5PXY]^ejx|ƗǗɗʗ͗ؗ'+4578@JN`cdj&+ߙƚǚʚ˚Ӛޚ˛՛"#'Ĝ͜Ӝ֜',19:?CN]ghlmuv{Ý{*/ٟߟ"#%&)*/8@AEFMNVW\^fgoptuxˠ̠ՠ֠ߠ %;CGIJQW]afkuyġšʡˡҡӡסȢszѣգڣߣ $%'BKLPYbw}¤äɤʤפ٤ ǥΥvzܦ $%-19:>?HIQRZ^histy{}٧ۧާ .16;@Eacfopst|}ĨɨΨҨبݨ $,-89@GLMOPXY^_n˩'(./68CDHIMNRluzªê˪`dhmy«ƫΫϫӫԫܫݫ *GNSZ_epstvhp ̮Ԯ}),ְܰ )*56<=BDGHQ$)1289ATbcfgnt{}²òȲϲӲFM "#%:=>IJNOVWYZagnpstyz!%)-7\cdfgoptu|~˶ն۶ܶ  !'<@ELchist}&-48<AQYZghmnrĸŸѸӸڸ۸ݸ"&CJOVWYZ`aijtuw»ǻӻջػٻݻ¼ǼYcžƾϾݿ"#+/<>BCHINOUW[%-;A$*+3=BIMRYu{ !(.679:?@IJL^a!"')1NWnu{TX pvw$%*4>?DFQnsx{|%(9@DLMYZbdk+124Y[\_pyz"CJNUYahos} $(3=>@ADEPQ[\^is!"*+07?JPRUV\ainvwyz}~ #  %6@ADQWXZ[`afqz{&-18<EIKLN`gitu !#3:BLMR L./]_78,-kl >?  r s { | >?XY78FGBC!!!!!!####F&G&''))**00D0E0004455K8L8g8h899<<-A.AMANAFFGGIIKKKKfMgMPPPPRR"T#TTTXXXZYZ[[\\]]bbccddhh_k`ktkukrrssttwwxxxx{{{{| |||0}1}4}}hi߀GH߂KL.ӈԈ[\ ͍΍EF?@Dѓ!"&78!"}~&>?CĜ"#ѝҝ֝{67̣ͣrs!ǥצئ)*pghڪ۪ߪ`BChcdh78&89=Ѿ4ݿxy}%pqz{@A ijz{>? %!";>&( /3LM69ciY[!UV 01 01"$<Amn yz &'47BDX[jk| )+JMceru 25SU`clnxy03LN[^iky|./EHWXlo !6:FGhkrt()JNijwz)-?@cg|}-.ILabmpxYY [6[\\^^ooxx 3R!rEw"/JsBSmDp.+ `Hkr&aqL +d) (hBj0jv&k~JsBS^`CJOJQJo(^`CJOJQJo(opp^p`CJOJQJo(@ @ ^@ `CJOJQJo(^`CJOJQJo(^`CJOJQJo(^`CJOJQJo(^`CJOJQJo(PP^P`CJOJQJo(^`CJOJQJo(^`CJOJQJo(opp^p`CJOJQJo(@ @ ^@ `CJOJQJo(^`CJOJQJo(^`CJOJQJo(^`CJOJQJo(^`CJOJQJo(PP^P`CJOJQJo(^`CJOJQJo(^`CJOJQJo(opp^p`CJOJQJo(@ @ ^@ `CJOJQJo(^`CJOJQJo(^`CJOJQJo(^`CJOJQJo(^`CJOJQJo(PP^P`CJOJQJo(h^`. ^`OJQJo(o pp^p`OJQJo( @ @ ^@ `OJQJo( ^`OJQJo(o ^`OJQJo( ^`OJQJo( ^`OJQJo(o PP^P`OJQJo(^`CJOJQJo(^`CJOJQJo(opp^p`CJOJQJo(@ @ ^@ `CJOJQJo(^`CJOJQJo(^`CJOJQJo(^`CJOJQJo(^`CJOJQJo(PP^P`CJOJQJo(7^`OJPJQJ^Jo(- ^`OJQJo(o pp^p`OJQJo( @ @ ^@ `OJQJo( ^`OJQJo(o ^`OJQJo( ^`OJQJo( ^`OJQJo(o PP^P`OJQJo(^`o(.^`.pLp^p`L.@ @ ^@ `.^`.L^`L.^`.^`.PLP^P`L.h ^`hH.h ^`hH.h pLp^p`LhH.h @ @ ^@ `hH.h ^`hH.h L^`LhH.h ^`hH.h ^`hH.h PLP^P`LhH.^`OJPJQJ^Jo(-^`OJQJ^Jo(hHopp^p`OJQJo(hH@ @ ^@ `OJQJo(hH^`OJQJ^Jo(hHo^`OJQJo(hH^`OJQJo(hH^`OJQJ^Jo(hHoPP^P`OJQJo(hH^`CJOJQJo(^`CJOJQJo(opp^p`CJOJQJo(@ @ ^@ `CJOJQJo(^`CJOJQJo(^`CJOJQJo(^`CJOJQJo(^`CJOJQJo(PP^P`CJOJQJo(7^`OJPJQJ^Jo(- ^`OJQJo(o pp^p`OJQJo( @ @ ^@ `OJQJo( ^`OJQJo(o ^`OJQJo( ^`OJQJo( ^`OJQJo(o PP^P`OJQJo( 30jL +d) (hEmD!r&ak~"/ `                            N+]         4#h1OGOOFRBU&J{^m=C-/-  ['M89V11#$n 'CDk *+de UmnMNjksbyz 0@''Ď'' hhhhhhhhh$h%h&h(h4h9hChMhYhZh]hahbhchihjx <@$&(.46>@LNPTlvUnknownZdravko LackoviKorisnikPrivateGz Times New Roman5Symbol3& z Arial5& zaTahoma?5 z Courier New;Wingdings"1 hF݃ #Ty#Ty!r4dZZ 3qHX(?BU.Botulinum toksina tipa A i kolinergi ki sustavPrivateZdravko Lackovi8