Proximity activated interleukin 21

Abstract

The invention relates to proximity activated cytokine compounds comprising a PD-1 targeting moiety, and an IL-21 polypeptide covalently linked to an anti-IL-21 antibody-binding domain, which together provide targeted cytokine signalling to PD-1 expressing cells. The invention further relates to nucleic acid and expression vectors encoding proximity activated cytokines, as well as use of such compounds for treating cancer.

Description

[0001] v roxm acvaenereun e useeureosrenrenvenon reaesoroxm acvae- comounareeo- exressn ces, s a an cancer. ,caon cam.see r ouneror o,uroeana.enecacons .e une e ovemer ,ncororae reerenceeren. oer , an . a-croaun anen esx sooswurne croonmseonns, m saucna ansn canc ceer.uonwceovenr, anereevreanenersunconn cronc amnsraonsme s sora-e aneoroc eecs,unccene o ssemc- snan on anen-resennenrc ces.aren unmmunosuressve aroaco re-nvoraeumour ane -o- exressn cess aromsn anens.ns con n-secc cesaaveeen cronca exoseoumour we ex, aenuae conesaveeenesneo mananereraeucenes arou msnmzn acvaon o non-are ces anoena averse eecs. ecrease aerora acensaoveee csocrnaee ceo usnee o re aceenouraee cnones.roue meusea aonsroaecsesneao sownoena,e asoresen a caenena aenuaon reuceseoe ve s reuconnoenc caneroemaceare ces, suc nc onare ces.oweves oearenroen.onseuen,er as- exressn ces, ex eraeuc ecac o recomn es aressn neeor nove oonsa manan ase one aove-menoan- we ensurn aeuaeoenc onare ces. an eecv ne sae oe ar,e oecve oeresennvenonsorove sae suec-maeer re ocomenannememnuennom coaumasor o ceonreese conm soeucnsc.aons, o wecuvreesr a aavnae e emomensescreneeenen cams, exames,ures ane naeous seccaon. neraescron os uemmnavern oone renaveenon moecue exresses onoer souxrmace o ac avaaree c ceo, annes a moe, c coommrrssnn a an mo-e caorenen cov aae- neano ann aen c-on-ex a onoroxm anoen-enanreeom n sn amnm.uneuc ces.ser eoxvame eensarnocvee coerenne esrcsr aesec moecues wc eecveever-o--exressn ces. an au oenvenon reaeso comrsn an an-- ano anen-nnoman arcuarm eamno-menos,eeenvenneors corvoavene ano- an- an a-n-o aensoavn an aene-avn cnanom vaarna.en v om aaneas-- sm aaeraso smar:o wc : , an a can varaeoman-- conac w aare ce means oe an-- e seeccve aenuae- snan un rou n nonna o,, ane- mos- coamrmeonn arrmesscrae armem coumnea ceec wc an on,no n oee nra wuor are. esnso nroovneerere w e o comnaonera aroaces, aownmroveosnex .n some emomeeoss comrses a non-ocn - ano varaeomanescreeren, an a conns,eoneo an ano nn oman seccor sa conen oreroever a meoeocuee e aenuae cone snanne asence o w cone s e -aren moe .e. a reuce o an anon aa on cesacn -, or w oce -.n some emomens,e comrses : , annen-,n rensecomvean.avn a , an a aeas encaoe seuence nnomanavn a , an an o aeera esmomens,e comrses an ano anen- , resecv encaoe seuence : , an unrner enocmoame n,a.snse asececnv oern socnv areorma, c coommrsn an- neo an an-- ano oman, suc ase varaeoman o an ana rsn an aernavearen moe ano eren ce surace receor onare ce ons an-- ano, or an ano aren a an vaenc, accornoose s .envenonroves w varousnaeormas, exurreesrs anse ocrs e oncoennve anno-n ree-a o ,eu anon osroeaexam nucees.c ac seuences, exresson vecors or ces es an- ano varaeomans anor s as anecrnve eern usoe enre nunr.er reaesoarmaceuca comosons comrsn accornoenvenon, eecveose or aean a ccacnocrer,nn aoeonnveon moen.os orean canceraens amnsern an erms anenons aoerner roua rraoes,eser omsn useerren s seccaon,eoown enons w a an wenever enon seor e ne snuar w asoncueeura an vce versa.ne evena anor s ow concs w anocumenncororaeeren reerence,eenon se euevearma ens c s “coonmro erer. os,n as”, u “seavner”e, “nc,o anraennnen”, an “ncun”, an oer smarorms, anrammaca a anem oremsoown an one oeeoe euvaenn meann anoe oen-enen em orems, or meanoeme se worss no meanoe an exausvesn o suc comonens,, an o on eseem orems.or exame, an arce “comrsn” on comonens,, a cnan conuss a oso o.en.e, c oorn maonre on oe cro cmomonoennesns,.,s a snuc,, or csann ceonnean a nno v unsceorssuoroe o eam “coommernsess o” a “nco smarormsereo, anrammaca euvaensereo,ncue er nssn essena o” or “conssn o.” oee a rane o vauessrove,s unersooa eacnervenn vaue,oeen oe un raowerm, unesse conex cearcaes oerwse,eweene uer anowerm oa snceo an an oer sae ornervenn vauena sae rane,s encomasse wne onesure, sueco an secca excuemne sae rane.eree sae ranencues sc oorsuro oems, ranes excun eer oro oosencuems are asoncueneoeearen vacee. ueo o “raaoruam” ae vearueer o sre.aroarm eexaemreer,enesnccruoens reanerrnescor “es varaonsa arerece “.” aou”ncuesescron o rese uresens uenreesns,nceu connexn ceear aecnaees c oamersw,se snuarorms “a”, “or” an “e”ncueura " conmoorn"e wnse wre us oer weroeunseo oeer.aenus a,s seeecrmce. " raencaoro"n as o us eeacn o aerawseo s sucec aeeaures or erensneneoncue " an," " or," ""aone, an ""aone.ewse,s " anor" as usen arase suc as ",, anor"sneneo encomass eac o eerm "anor" ,, an ,, or or or or a eoown asecs:aone n an an aoneaone an conmemss. one unneer osoeorwse, on ae oec orncnaar a sn scnene acreer.m.s, uns cee ceureunre, mavoeecuea sramenee mcesa,n nnuc as ac cemsr,rzaonecnues anocemsr, oranc sness.anarecnues aec useor moecuar,enec, anocemca meosseeenera,amroo e a.,oere onn:aoraoranua, e. o rna cuar .. an roraoraorress,ornaror, an c usue e a.,orroocosnoecuaroo ,one ons,nc. eeremmca meos. uman-- cooeene conex oeresen seccaon reaesoe maure, canonca eoroc roes smnueano cees suec ansro ces, ce resues-.- oeesave oee smar encomasses varans o-as a,r aen a neauraer ces.eerm- - seuence an r as encaoe canonca eermsumanean aeas osooca acv. - receor mae- o reeceor,- ne conex oeresen seccaon reaeoeuman amma can.e receor-easαo a acav caaonnnro n aeeromer we common , an resusnroeraon an acvaon o o mu ceownsream snan moecuencun reaeeesrmoaev mna snuusnacnona o ane sa-me coooncea,. aec.nve a as ns, s- ces nan an ne coown c nee sxs re o. ame oreesennvenon receor-.ere reerenceo aercenae oeoocauncon o an-oumeane-s v maeere an,errsea acmevnseermne eermnneercenae oosorae comareoreamen w o recuorman caennuem ces, aerreamen oe-oeeor an-r-,eresene as an vaue, as s eorn onxa e accoome cae acn. vven oons- aesa mseasur,ea wrcuoar aeas , morearcuar aeas o. nnomanne conex o a .oocau ac asvsoc oao ann w an an-- ano anen- covaen assocae -oee,a maaere eerm-ne w cone axn ooeoreorm a . e ene, aso somemes reseern seccaon reaesoeuman-roen, encoe eeermene-n,e as coon soemxe omees rereesrenre soec ascaon reanesrooeuma.n-roen, encoe eermroxm acvae conreo as nro .mmunoconuae,.e. a recome ne conex oeresen seccaon reerso an moecue-aree anonnnaonoee moecue comrsn aeas one ce-surace omansscoseeren, assocaman, suc as seecerom an-- ano anennn weren sa an-cone anoe an wen ann ann-cone ano anennnoman, an cone.ovaennae oe coneo an anooommaannsas ce covaenneosare aenuaesnn oe coneos conae receor.n ceran eman seccanoe cone anen-nnoman oe acs as aarenoman, annonme ons s,a an c an-- anonaes aownsreamunconn aaremmune ce exressn -.n cer oneoe ce an-cone ano anennnomanns seccao, an aenuaeasn eem somens,e -oee.xames oareso wce ce-surace moecue-aree annoan an o, an nnoman man one ce suracencue,or exame, ce surace cuser oer en marers exresse secc ce suses, e.. on ces,nerns, anen r enaon co-smuaor moecu eceors, anor ceoenrem re cceoonre e rxeree ers ss. seo a on maeur cenereunroen, or a varanereo, caae onno a suc as-, or-.arcue surace o anmmune ce, annan aownsream eec, oee : .ar eemeormmeunr oer a en ccoomnaesresenenexamesse-mrove sa or snanuaes, examesncue,sues ar vear nan coneoees w comrsn aeas one muaon, or cmerc- varans comrsnomeo, muens o- cones comnnoeeserveromwo cones, s eeons,nserons, or cmerc en onensaar . uc as- - cmercroens eeu scue oen snc eceesse sremn aarre o arsoomaoroouse.., aeas aou seuenceen oe seuences aceve cane aou , oenvenon.n some emomens,e seuenceen ae amno e nucec aceve,e seu,ence,en, can,e a,ou,,,,,,,,,, or,er., v nuce,c ac, sem,ens, w,rze, or er.ernave, susanaen exss wene rzaon conons,oe com unemer seecverzaon cononse.., ver srnenc ces,n a cesae, orn aaraureen oe sran.e nucec acs maeresenn woenene co reneerxo o a senreesenuan seacvceaoanra, or mee su erer rms esan re ssea enuennucreeo eernm. resu anercenae o seuence eermne comarnwo ane seuencesoson oson. oe a soeuence comarson seuencesor comarson are we-nownne ar.nmen o seuenc sor anmen o conuce eocao esor comarson mae eo moo aorm om anaerman,v..a.: ,or smaar a mnemeon o aoerarsmo oeeeman anunsc,.o.o.: , e searcmemenaons oese aorn amns,ncmuann,,roc.a.ca.c.: or comuerze an .owareorerorm u nomeo: , , , , ao n anasessuc avaae, e..,rou e ne enxaameneeroro cromoaercsonoo-normaon :as.nc.nm.n.ov. sens:xecreso:n oo armn soze a:c seaxuencesse aorma useseeau oss:xsence,xensonomosona m aacusemsenn as:ueor rane:arx: a ausmen.ne suc exameor comarson o nuce nona comosona score marx useseeau sens:xecreso: orc s acze: seuenacxes msaceesn aorma acsmaccores:.-a coss:near.ness sae oerwse, seue auer rane: roveeren reeroe vaue oane usne sue ororamsnscceu een a., vaues o.:- usne aoveeneeauarame .o. comarson ersorroen an nucec ac seeeureennccee, so res .e.enec ec save am see. sueenucees wou seccaon o aercenae vauemes enca arcuar emomens mae usnece o.e seuences asscoseeren.e. enca. eneraocemsr:ees,mnoceuences moerermoeene conex oeresen seccaon reaeso a moecue conssn o or ee am amnno acsaorm anear can werene amno acs are connece eeons. soooc ac seuence o aoee ma reresene amno ac seuence o a woeasounnercaneaaeroreen orramensereo.eerm "oees" an "roen" are use as amno ac resn anncueroens anramensereo.oees arescoseeren ceermee oure o seoueencese.ne conex oeresen seccaon reaeso a mo aocnssn o uo amno acs,narcuaro amno acs, morearcuar o aemcuneo mnso, acao rerms anear can werene amno acs are connece eeons. osons reeroue-a smenuoen access arneeve onner-oeme arm conoeo carreor,xoecrmemnussr.,ardea.e.ers.oro sweeure cnacsee v aeree wrsroern amenoo ac r senueneceroescoonnsr roemeroe aem corresonn- or-amno acs.euences s nooe caroxermnus.n accorance w snaneare neorm coeneca asuren, acmaneo a acso reoswsu:e saenunences areenomnae eer areeeer or a sarccs, ea,,rnner,,saranesn,, snes,,s,oeuscenneee,s,,,euucanmeneeu,n,,,suamcc u,,cne,, renaannee,,ronero,,erneer,,reonnenes,r,,,eroonnaener,,,, roeos een rrme es v.arr,an, c r aen ae vrsa aron an ae ooa, ae. oeeaeeerrssrnoms a rremearernc aemnoo ace see,ueunc reearons essena reerenceoee.enera,erences areme soae seuences oem re aneorer, oee ane varan are cose smar overa an,n man reons,enca. varane ance reerenceoee ma ern amno ac seue n susuo nce one or more mocaonse.., e one enns, aons, anoreeons. susue ornsere amno ac resue ma or ma no aec varacno,e or eenec coe. varan o aoee mae naura occurrn suc as anne conex oe mareseen a v sareacncaaons, noeenrmowno occur naura. ne conex oeresen seccaon,eermmeorm reerso a un conssn owo suuns. suunsa are eerenca or are smar memoersm oer reerso amer comrse owone conex oeresen seccaon,eerm amno acen saemre or caess oe suuns. coee o varaeen as useo connecwooeesn oreroenneerra reee ars sno ae area onooee.xemar emomens oners useuorraccnenvenon seceeren eres neo cones craanns o cnonses amnn oo ac,, co,,,,,, or amno acs. consss o amno acs seeceromemroouson oener.n ceran emomens,ener emomens,ener consss o amno acs see oce,ro,m,e,r,,,,, an.n ceran caracersc oe conuaeeeners as sece aove areoouwm omun, an.nmoranen a aowseomans wc areone ener,oneracoorome anucnc, aonna a enee scoseeren.narcuaresrae emo as se mens oeomaneeners sece aove,e munenc ees arermar mae u o sreces o amno acs suc ascne an serne. non- oreexame o an amno acners a monomer or-,r- oreramer o aee mo comose acns e wm ooro smu mer anrsc c rene ara a acnn o ersene se cs aern re ene. xcersan ase,scoors eexameree,n,e en acomass srucuresn wc amno reace,, or, an mae reace . mno acs,,,,,, or ma eneraoecuaroo:ucec caeaeerm oe enneco reners ao aarocunaurcec ooeee counen eac ones rn, ro axr eneeass aso e on rnee onenra rnesacrnera amneransaea.s v oenenu wceo we seuence cane useoen arerramens oru-en con seuences oe ose o s nc e are assocae.eos osoanarerramen seuences arenowno eerm e ar. aseenrraannssenene conex oeresen seccaon reaeso aene orenec maeraaranser oe nearrerom one oransmo anoer.neresen conex,eerm ma aso reero weres mssnu.ra m orausroeor rca nac varan o aenec seuencenossue o aaen wcsrven aromoer asene oerr soranser o a naura encoe seuencee exresson o nraoeuecrm o re ocnoem orn saenvenra see cosn oex c oonneenc , rre eessen rnc se one acar nceae orona rsesu oae ne.s ano a w nuccesc acer,e wncromsee oreura oerm os occ ,eu enrern r eox n ceru sec ssese soc -n a an ocr e.xror ree usc csom son,n e oa rrn e a v oe -rr onuasvaercee coemrmrseense a rreocoumc, mnaan r neuecreoc e ace.r o, o ae e eneraon o nucec acs oreeneraonnermeae orroceose e, aso reerreoranscron anransaon, resecve, or an oe eermene exsreesssoan r meaua aeserocessn oenecnormaonoe oe eroucs. rouc,or exame a reuaoroe a ore a soruceuraransec.r.on an rocessn o a ene onuceoeservero rosoma . an exresse e menomc , exresson mancue scn o e m n a wuorars moc ce a.nxresson mae assaeo oneeve oranscron anransaon,n oer anaeoerumeuucenooer osr cnoen s, oe cr ooo mnu eec rx. s o o wecr aersee cn seccaon reaeso nucec ac or nucec ac oomers oneas aae oormn seecve rs w or ronuceoeunso ocsa aseenoasrnne,. eerm nuceoesn s conexncuese cassc eoxronuceoeseoxaenosne,eouxanuoasnne, urnean ros mne, c ne,e casscurerncues anaoues o nucec acs sucos anse,osmoneo,eoxurne aneoxc ne. e e nucec acs --am aes,’-me osooaes, nuceoase aa noe -cne unsne e enae, w e me enereceouen aoac-casr.one oreveer reecrennece oroce nucec acs ’,’ suc rzn seuence mae comose o an oe asov mea nueceeoreneso, a rzn seuence, eerm nucec ac exresson vecorne conex oeresen secca oorn m rxuresereo. a vraenome or an , wcs useoransecn case o aasm or aneae osrroan asuacsem, case o a vraenome aare ce w a cerane n en ne oneres, or -ne case o an consruc vecorsra onsereace-oransaee corresonn roen oneresrom aransece m .or conro o aronmo oneeve oranscron an suseuenransaon,eene oneress uner eene oneresers sreanuence an eromoer seuences oeraonanseeare ce,us, ce’s saus.n ceran emscorem eer consuve orn resonseo a smuus oreenen one vecor, wcs aeoransuceenes,aree v crea.enomesacaeno a casoecome a vra v roenuecrmeo mesan cean coneexro ocesseerese enu sarecoeca roonso remaese.soe a monuc ceoomres conssn o seuencea caneransaenoe encoeoee seuence,er es a con recomnan cone anooee asescre esewere e an anooman, or an unransae reon’ a asnsnno anroceren.e m aso comrses aarno reon. m ma comrse a’ ca-meuanosessn e rosome“nea reon. ne an a’oaenosneo n non secneers m,oans,noes: ans re narrowneeaeescron oenvenon, reerenceoners an ara encomasses anoes, ano-e moecues an aamers aseneneoown8oeeer rramar ss. eec wc an cenrann aen con anex oaree sreecsencn.veneo an rneer os sou acr aoear oansan msosocaoanrc cuonasran ≤ o-9meoan w.en snecncao resacarvee,aun aasss aocassooncanons connscaane o ≤e- orers o manue ernsneracon w a moecueav consan aeasree comoson aseare,u aerenree-mensona s n aoa smar cemcannowen connexe a or oe creesmensr s aenccaosn,csee rermersssoo acnaru eocnu u croen. rsuman cDs usens meann roens o a comex comose on mos cases,w onsana measuresenos consuen comonens. oeren comonensossocae revers o ano an anen.es comex cane e.. an ano-anen comex comose concenrDexressen moar concenraonmo an corresonsoe concenraaoonn o a wca oenn ses o are occue,n oer wors,e consan can oe ca uncuoaune accor enuasoeeo coonwcennraormonua o:e comex.essocaon com: ceoxncenraon o ano : : concenraon o ano-anen anre ues ceonnexe or meearnensen seccaon,eerms o-raeoffsec an on-raeonsec*mo maeasurese nownne ar o cemsr an scse reero a rae consana c ssocaonoffor assocaonono an ano wsare anen.offanonene e axnermen oa ane anermone e umsno mse suorasce wea essmaons reesonanncee. ar.s mseeoronrceeermennn oesenof ssf soorc sasoneomn cosn ssuacn asDe usancoree ooroeroen ssem.e can asoe useoeermne ^w ^n-ormua: ne conex oeresen seccaoonn,ee9v e naura uermore on-raesrsec*mo. meo m ano reerso woe anoesncunu no anen-nmmnunrooune ,e ,e ,e ore , ans acoroen caomen, or sne cansereo, an reae orerve consrucs. woe ano sueons.macrsneav a ceaasnwso comeavrs cans anwo cansner-connece can consan reon .eeav can conesa on r aeeoanv o can varae reon an aeav an .ac cans comrse o a can varaes r ceomonrsaer oevareeeoemreans,H, anH a H can consan reon .e can co n as e va nsan reons comrse o oneoman,.neracrsa we re anon asn oeneeav an cans assocaeo creae an anonnomana comemenareermnn. reeonnsn s.ecec o as seom anemoes rsareeermne e can , -, oreeav ca eerre eroson one esnanerosonn n , -, an er numer,, or enn amno ac resuees vanraeeoman reon. no oerwsencae, numern ssemsnernaonamunoenecs norma reonon sss aesm u,sens seccaon usee sanar s erenromose assne uner aernave euv waenc nue seerson w reconze are oraa.mar, were seuencesene a varae anen-mnernn c sasnems suc asoa, areven accornoe ssem.uaonsnecomana coner,c reeceo sre sueennces or enance canarn, are name er c cn, re ommon useaa numernaes.e consanncuonsn o vareou asn coes ma meaeenn oemmunoounoosssues oracors, comemen sseme.s oemmune sseme.., eecor ces aners comonen oe cassca an anoramen coenserm ano encomasses a so-cae nanoo or sneoman ano, eerm ano anen-snnn o ao smnane mnoneom coenrcex va oraee a sneooman. aeav can varaeoman seuence, an a can varacecaoon reerso a comnaon o wc wen assocaerove auncona ano anen-nnmomaanno seecceor seuence, ocn - eoes oenvenon.s maene e non- oee assocae w a conex o au anoeav canne conex oeresen sec ccaanono,eeerme, orar ameernna cvres, an scv. meannnownne ar o ceoo anmmunoo reerso aarazcaone o acn reons usens aeo,woencaeav canra ano comrsn, n mens conssn o aH an aHoman, covaen aneen, comsursneoen cosn.saenermaramena reersoe reon o anoansone conex oeresen se acnca vaorna,eeoemrman ssn oe a-ceaav an canar.usonroen oe varae reons oeeav ann va craanesram oen anscmv reaeso a resunn an ano-e, anoear munooun, cans oe scv ar erom a sneoee can.e an e a. . e conne:ce–rou a seonrenr cearne eeer c ooneno aou amno acsuson e-ermnus oe -, or aoe reverse conuraneocne--e.rmnnuse o coneex o we v s vaeccaon,eerm sne-can varaeramenscv reerso ausonroenn wce mornaoceon rae aonnso o are can, aneav can varaeomans oearamen o aonnwo or moreares ooneeav a mneans o c aaenxoemaenseneer.eunemres.rc scv cane creae enanc ncomeer caom snm se axun n a ooer en,ea arrecsueanr s ane acncaoon,or aeneorm- ane- mo-e anaons anos meano cascaeeano cenon aer ce acvaon asar oc wuea csanaowen onsrune sna cecon mecansm.on-mn e aremmune exeme e c examesncue anoeso- nro , -,emrozumancaerc avanca.e anoo.rus n-vo-um,aosarrso-ersu o - , snma ,nnoenoocs o -maesaro o -- --, cemma o --, cer -,sezumaeene o o --,orama o, -e-ma o --, sasanma ezaenma o --.n-- a , zeuvama o -- or receors- an-.nn o-o-na anons a-nnoessn ce acnvano on, surv-vaoe roeraon.n an-- anaons anosru an so-cae c ss sna reeaseeraesrove s sa urmseaceueercec an,on acen ceeramon e sa n aremaa ecev reue oce ,ae o ceoamc. ero wson a reeaesrs onoe a caormmacoun oenvenon, or an ceran emomens,earmaceuca comoson accorno euca acceae carrer. suaeoroca, envenonsroven aorm s usee arenera ornecae amnsraon. coans, surreanc,anes,e armnoxaramnasc,eurecsaerva acvceesaore ex caamrrere,n acnueasc aenra s aoveennss,, ansuenrson mea,soonc aens, asoronean aens, sas,reservaves,rus,ru sazea aens, excens,sneraon aens,urcans, sweeenn aens,avorn aens rs,ners, comnaonsereo, as wouenownoose sene arsee,or exa,mees,, anee an cence anracce oarmac, . emnon:e seeaseerm ceanecremrs as “c uasnecer”n ane “m coanenxan o neeoaresen seccaon reaeso manan neoasc seccancue carcnomaeeaerve casncsease” are use snonmouseren.e moma aneuema,erm-ceerv cer, sarcomaconnecvessueerve cancer, asecs an emomensscoseereumors anasomas.arcuar aernaves o an oe oenvenonnreamen o soumeorn arerece ae use oe comouns an comosons scoseeren arerece ae use os.e cer aernaves o an oe asecs an emomens suc as meoenous orranuocceuomnaons oenvenonnreamen ou cancers moasceuema anmoma,oceemmaa, vearar ocru earrema.,mac,mocc, or ems uosemeenr,eno, aemeeromrarneane orsreeaasmee onr os aonrerseea.s.e s orowsnor oerr aer.re.s cnance orr r reeeurcsnn onee v "erevaeonm"e onr " oreameens"ea reseer osr ao aeaesva onne o or amee conrcaan s ameoamss oereo.n anoer emomen ose wc ma noescerne eaen.ne anoer emnescaarameerncun reerso mouanesease orsorer, e omen, "rean" or "reamen" smom,sooca,e.., sazaon o ersca,e.., sazaon o ascernereamen anorrevenon os ascaarameer, oro.eosor assessn ereneow. ease areeneranownne ar, uness seccaescre e evea ene ovenneosncr roxreo msenn oee cvearneve enn aomnsoonencrease coem saoeun as.n eesceac o a recomnan conearen a ce memrane anene..,- an a se comouns comrse one arm roen.e cone armncues an ano s con armen an ano-coneuson se, omzeooc ssemc cone snaecnca wennoe cone as receornn anosoun ermn snan wenesecc rs asec oe ce memrane anen.. caae on onenovenon reaeso a comrsn an an- ano anennnoman varaeoman --, c aonm arns-n aeav can varaeoman -, an a can oee.e-oees cov-aen annoe aonee enenrn-oman, an auman- a sne conuous recomnanoee can. -, ore--,orove ee-n-v-eno crn osm enxrsoornema a an voa arnee oe aen- a-ea-o s aenoe enescaooeerem sneeueanc aeeav can: vara aeno aman can v:araerovomeasn-- comrsn aoee aeas encaoe seuence sn coser eecve aenuaon o- snann varousormas, wcse wene emomens, oxmo a- cerovn moreocuse eecs onare ces.n some ooee aeeas comernsecsa an an-- ano anennnoman-- conssn oee aeas encaooe see seueunecence ::., an an-- conssn o a omeannvenn aor vsarouna-oees maeneoe an-- ano anennn -ermn e oormas,or exame an-ermnus oe-- cane covaenneo a oeuse o can-e eomee aeener, ore-ermnus ane-ermnus oe- can.neaer case, seouen a comemenareermnn reon oeeav or avn aoee aease coemnrcase aon ane- s- ano anennnoman-- conssn o aoee aeas encaoee seueunecnece ::,, or asn se-- en reaesoe ano-erve seuences on, an an-oees anneruence emee consruc are noaenno accounnerms o seuenceen. sn an v annee ansecn oneomnvaenn,o ann re aanes ano- a-rox amne ancvnaen coomanen covae comrsn an an- oee aeas encao :.e an- anennnnnoemano co amnrs- aneav can varaeoman - a es a n a can varaeoman - e an-- omaennn-n-o.mane, co-mrosese aeaevs c can varaeoman-- an a can varae e c ovaenneoe-- oroe--. sameooomcars aecs avn-oee aeas encao :, anavne emomens,e c oonucn snan as recomnanuman-.n some emomens,e commrsresses an-oee conssn o :.n oer :, a an-oee seuence seeceromerou conssn on ce n . omarna cno emmrosesm aenns- o-e com arcsconr anoe sneveecneon,rome ane-ro-u c aonnsson anennn an , an a seeceromerou o : ,, an an a s conssn o :,,,, an an an-- comrsneec aneromerou conssn o: , a:,,, an seeceromerou con n annarcuar emo ssn o :,, an . comrsn a mens,e an-- ano anennnoman comrses an-- : .: , a : an a cnom oresrnar acuar emomens,e an-- a:no, a anennnoman comrses: an- an- anarcuar e : . comr momens,e an-- ano anennnoman comrses an-- :sn. an : , an an an nom cearnan co emmrosesme anns o--eo acecorenaovne anveenon,e an-- ano anennn ae, orae comareoe seu as one amno ac susuonscosen an-- ano anennnomeannce c :.n some emomens oe ,e amno ac susuonscosen omrses an-- oeeavn aeas one some emomens,e an ae, orae comareoe seuence :.n susuonss -- ano anennnoman comrses a comnaon oe emomens,ee ann--ae an coom anareeo : an : .n some .n some emomens,e an nnnoman comrses a an arsenae sen -- ano anennnoman comrses a an ar e comanaeo. co ns o muaonssenaes, anorrove cones w aere anor- arrmanaeremenoseonunsee s-eueoncee oeoe, w anc- e-na ane cooma anen wnnereonmaen, anenaveer v saveosurnaee manu.acuer rnesu anneveo sae-uareosm suncer aasc aonasc w o coess-r oanseraoanna mocaon ces exressne- receor -arene cnercaan, m emoreoamrecnusa,re >--. en ccoansos sse o aoee aeas enca,arcuar > aneaarsc ounaer a emmnoo amcen ssu,seuoonescoese aenausence ae, ceonmcaareo: oe s. ee sueenuceence ::asnarcuar emomens,eoee ae . a comn as encaoe seuence : as .n maon o amno ac susuonsscosenae, comareoe seuence : : sor seeeacrcuar emomens,eoee aeas encaoe seuence ,,,e,rom,e,rou, con,ssn, o :,,,,,,,,n ce ,,,,,, an . enrcaan emomens,e-- consss o aoee aeas enca,arcuar >narcu, maro eremaorcmueanrs, >eoeencaeo seuence :. aeas one amno ac susuonscose aenas encaoe seuence : asn oerarcuar emomens,eoeea aeea, comareoe seuence :. as a comnaon o amno ac susuonsscossenencaoe seuence : :.n morearcuar emomens,eoee aaee, comareoe seuence n: s seece as encaoe seuence enve romerou conssn o :,,. aovroseee armoneenaammeun souesncuon n : rsoson o o oe resecve varans.us,n an vssuen ceran es woumacnenn s aran oe - nnoman,s susuon assea:-a e asce e ovnco a oma uraesse. cen accornoenvenon caneneraeeermne eoown ro.r.enere e sa exressnuman-envenors use a cenerove enera, anr cenvneers w ounenna, seeuz e.,ncoare ,a , -ore assa are mananen con ma--a snan exressn- cane emoe enre.or acvaon, ces arereseum suemene w ea-nacvae an m.ers smuaon, ces are wamsueaew ocveern w nm anonomcn meum.nea oe assa, ces are coune w an rese overnnresrow oomae.- or-- comouns are a an seee a.×⁶ ceser wen a-we- °.oown smuaon, ces arexe w oex anncuae we cesor mnues a osowermuer, an sane w -conuuer oscences,ermeaze usn oscences,a or mnues a roomaeem aenra-urero anocone , wase an resuseneor anass on aow comeer. ecerom .es are vne om soamne- eomn eson nom seonm nsa on caneme aeccore snmuoaenvenon,e an-- ano anennn vo- ce.s cane c neousnn oemrozuma, or nvoumao a n onrmen a comeon assa werencuanemrozuma, or -um anaooe anere wn an cne,oomesan noor smnncaanr one susoe sauen cenon oe resecve an- emomnens, an comeon assa u r vce versa.narcuar morea snrencuaon wemrozuma, or nvoumaves no comrsen em aoomen von o nn. n som a esr oans e aee accornoenvenon,e- comrses a varaeoman comrses a varaeomaas encaoe seuence :, ane - :.n some emon comrsn aoee aeas encaoe seuence a ceas encaomee snesu,enece- com:rses, a an varaeeo-ma cno cmonrsssesn a o var aaoeoemaennon csesrann o e aoee aeas encaoe seuence :. comrses amomens,eoee ae:as encaoe seuence : : . , a : an a cnom cerrasens e amnomens,eoee ae:as,encaoe seuence : : . an an an cnom somrsee esm ao varmaenes oomaen com acrcsornn aoease onnveen amonn,oe ac s-us ouoens-coaren moe comareoe seuence : ane- comrses a vara senae :.n some emomens oe accornoenve eoman comrsn aren moe comrses a varaeoman comr non,e - oe- ae comareoe seuenc sn,,, or ac susuonsscosen comrsn :.n soeme e : ane - comrses a varaeoman comrses a an ar momens,e an-- ano anennnoman cnon ssomsen em oomens o:ese , an ancceoaren. -o coemnvresneson a,e- comrses a varaeoman . varaeoman conssn o :n some emom veanrsan os com e accornoenvenon,e- comrses a varaeoman comrrssens a aoee aeas encaoe seuence : ane - :. varaeoman comrsn aoee aeas encaoe seuence v cnom cerrasens e amomens,eoee aeas encaoe seuence : comrse ens,eoe: : , a : an an ceran emom e a.eas encaoe seuence : a s an :, an : annn some emomens oe acc:or. comrses a varaeoman comrsnoenvenon,e - oe-aren moe comareoe seuence n aeas one amno ac susuonscosenae :. : ane- comrses a varaeoman comrsn cnom oaerre emoomeens,e - comrses aeas one amno ac susuonscosenae susuonscos seeunence : ane - comrses aeas one amno ac e accornoeanev comareoe seuence :.n some emomens o oman comrsn aeaenon,e - oe-aren moe comrses a varae seuence :s a,,, or amno ac susuonscosenae comareoe , or amno ac s nore - comrses a varaeoman comrsn aeas,, some emomensusuonsscosenae comareoe seuence :.nn ,e an-- ano anennnoman comrses a an arse cnon ssoamee e.momens oe accornoenvenon,e- comrses a varaeoman .sn o :, ane- comrses a varaeoman conssn o : -nnoman ann c aenrano em anomene-nss o n o cn neca u oman asec oco arnn- a anon aoeo nsnevs aennon,e sareeo- ces usn nvouma.n some emomens oe a -- ano, suc asemrozuma or varaeoman comrsn or con ccornoenvenon,e - comrses a oman comrsn or conssn ossn o: :, ane - comrses a varae envenon,e - comrses a vara .n some emomens oe accorno ane - comrses a varaeomaneoman comrsn or conssn o :,n ceran emomens oe accorn coomernsvnen or conssn o :. -erveromemrozuma, nvouma,ro on,e comrses a- an a- an an-- anennnomanneo aoma, zmerema, or , assocae w comrsese - an - oemroznum-a,oee.n ceran emomens,e oee corresonso an-:an--oma ann o ae co-- an--neo an- ae.n ceran emomens,e comrses moun seeceromosesen -- an--neo an-oee coerreso-ns aon an-- o nvouma, ane comoun seeceromosesenae.n ceran emo :an--oman o a an -- orooma, ane-- an--menns,eeo an com-rsesoeee- v c corresonso an-:an--oman o a comoun seeceromosesenae.n aenran- em-omneens,o aen comrsese - an - o zmerema, ane-- seeceromosesen-aoee corresonso an-:an--oman o a comoun - o , ane-e-. ann cer-an- emonemenos a,ne-o comerseese - an -:an--oman o a corresonso ann c comoun seeceromosesenae. meaenrsa on a enm anomens oe accornoenvenon,e sareeo- cesama can,o ens aunen-nnomanerverom an anaons an-- anoavn a aaa- .n sormne c eomrreocm arnn aeeroeramercorma w an--avn conssn o :, aneens,-e com-rs comrses a varaeoman comrsn or o :.n some emomens,e -es c aom varraseoman comrsn or conssn conssn o :, ane - comrses a varaese ao vmaraaeoman comrsn or o :.n some emomens,e - comrses a varan ceomomrsann or conssn conssn o : ane - comrses a varaeoman comrsn or c coomnsrsn or :. sn onn seomeo e am-oermmennuss o oe-o acceorneo aeenveneon, an-ermnus oe--s covaen ane ner.narcuar emomense ano emomen-s, areenoenres- a aeener wc as aen oo amno acs.n some emomens reaeo a mavno acsnen.n some emomens,eners4.eran , or aen a.nn-arcunaer emoo anm aenn-s- as annoaen consruc , or .n oer emomens,e com,reses, or c coomnrses, or consss o aeas encaoose o , or sss ooeesn some emomens oe accornoenv . oe-oee are emee wne comeenmoenn,aroe-ermnus ane-ermnus -.n some emomens,e-oeesnsereeweeeernmnen an reoon c oe- ceaveeweene - resues an resues a, or corresonnoe anaon was an- em:eeseen an an-, or- aor exame.eran emomens reaeo a avn arcuar emomens,e comrsess a,n onro coaen consruc , or ae.n e comrses, or consss ooees anesasss oenca or .n oer emomensn some emomens,e-snsere wne varaeomano anoses o sanwc or . eener oo amno acs a eer eeween a em en.n ceran emomens,e-oees aee wne oe an-- ano anennnoman,recee anoowen oer eeener : . canommano ameen rse,s emuen o-sne -eweene resuesne varae em:om.esnese reaeo,es, or a a, ae res vn an,ues cor - eme,resonn en a,ann n an-- or w as ano a nrn o eaxaemne o c.onesrraucn v emom,ens,e, com,rses, or, consss o, or ae.narcuar or .n oer emomense comrses,, or conss,s oo,ees a,eas ,ne snomcae eomoosem oens oe, acco,rno,enven,o , or . - ano anennnomans covaennen,o an a-ermnus oe-- oe an- eener.narcuar emomens,eeeneras ae-ermnus o-oee a emomens reaeo a avn an-neoe as annnoa oo amno acs.eran .narcuar emomens,e comrses, or consss en consruc ae arcuar emomens,e comrses, or consss o oe comoun .n oer comrse wn .narcuar emomens oeoe acces aeas encaoose comrses an c.narcuar emomens,e comrsornoenvenon,e muaonso enance canarn asescren r es an cavnno-n-oes arcuar emomens,e comrseswoeeerences:we, ercan, .n e o an an-- ano, enneereoorremn aes,e o an an-- ano, an muaonsnos: , oes: , , ,eromeraccornsneronnos-no-oe ssem e numern cnon csersa. sn o emeo-me-ns oneeo a accoormnan,o aneneven-on-,en aen-o- a anomeannnnomannarcuar emomens,e aHc1cornoenvenon consss o oneL. oman, werene-neo a oman, ane-neo a an-om aanneunrenn an-- anennnoman w H1 L r one en covae e-oee aeas encao : comrsn anrs anne seoe an-- anennnoman, an ancoeeomanuseoe- conH2-H3oman.eermnus oers an seconH2omans anennnerommnauns, r oeseecvHe1.omasns oee: an va-enc anenusnrane oonmaen u aneree a cnor-ne-r o an o.. rer emomens oenvenon,e consss o one an-- anennnoman an cs an a secon an- anennnoman.. sows a numer o suc: vaenc snons ecoanrrucc aus na.r- em aonmeennsn oneo:ma vnasenscneo,ee--eerrmmnnuuss a orse aH1oman oers an an aermnus o one omansuseoe oe an-- an seconH2-Homan,n oerarcuar emomHens oe: vaencL,e-ermnnennnoman. an secon an- anennnomanssneoe-ermuns oeH1oman oers oman, an weren aermnus oe oe an-- an us ars an seconH2-Hermnus o a H H o one an-- anennnoman. ennnomansuseo one vnor ceran emomens,e as an an-- moeo an--:- moe vaenc o:see : ex-am meoe vaen,c or o .n oer emomens,e as an an-- moeo an--n mn ce uaarra ocn nu e samr emo ,omemnesn, ,s,e:se ec ceomor e acocrrx orosa nem n os, oer oe con essse ncs o. umc as c e aonmouncs wecn caoneans.c sencnn ceran emomens oe acc rn ssem. somemes reerreo as ase ornoenvenon,e s aeeroeramerc , aso ano eav an caneecrocm aenr co.n some emomens,e comrses ars an a secon ano eav an canom anrsoneee an-- ano anen-nnoman, anen-nnoman.eeav can, ore can oroem aenr comrsn e an-- anooe- oe e.e an--oron an e an-- o-r-on ooreone areer covaen ne mae secca assocae w means o arossma arranemen, aa oeramerc arn, or oerseccormasnownoe seerson.uc meos aamaeeromernen ,en , an nsc ,ncororaener enre canereenoun re,eorre enxcaem.e encooresr, a csese,c ex oresesnnvenomona rnesa oersmomu annoscoonauea neusc aeccco arcn enocoennveenon one oe emomens oemmunoconuae asec oenvenon.noe accorno an reaeso an exresson vecor comrsn sasoae nuc r asec oenvenon aos ce comrsn sa nucec ac or s ec ac.envenonurer encomasses nucec acs comrse a exresson vecor.narcuar emomens,esoae ce n an exresson vecor uner conro o aromoer oeraen a mammaan no.er asec o aesn sveencon reaeso a comnaon mecamen comrsn an an-- anaeonn an one oe asecs or emomens oenvenoneren, an nnvoaurmcau,are emmroozmuemnas,oes aans rm- ano a, s ann.amoans,s anezoumas, c seemecemaro,m cereemas, conssn oorama, zeuvama an ezaenma.n morearcuar emomens sasanma, osarma, zeuvama, sezuma, ezaenma,orama, c,e anos cemma, em anaerro erema, nvouma orn nc-uzu namr ea nm.oommaenn ws oceo ceosm nona sonn mceancamnen,enn c oomrses an an-- ano nno -osve ces, suc asosescosenaes an. nvouma oremrozuma e emc reaa or, c,re o wam mrnen sne an a scmo me nes oca u ernese oreseenanveenn aonn ese ac mveeoos orean cancern aaenn nee e aove asecs an emomens oeescron. e o anmmunoconuae accorno v cna sonmse an emomens,e s aeeroeramercmmunooun caracerze woeav oe ewaosn c.an.s,n on oeearr e om wocmenorsm,s an- nn an ansuseo an- ano nn a ce-surace moecue,arcuare an as csooncsss o avaenaren oman eeromers o an an-- ano,one means o aeaeenaerr oo a secavv c aonmrs can - ano eav an can varaeomans, o n an-oona means oe ne o wc an-- omansone no-ern asnec oomaenn avcecnorone n,nso aerso en c a von em- nrosn,no o ar une sveoue nm. aa,aeemnr wozoumsa rec neovnn-o cconncur arn-reamen w an an- anaons ano seece en emrozuma,o romes conssn o nvouma, zeuvama an eszarma, snma,sezuma, cemma, cerema, sasanma,orama, osarma, zeuvaamean,mas.eznum morearcuar emomens, e ano s cemma, emr a, ezaenma,orama, cerema, nvoum nvoumeo a or norz a ausm ,ea ec. m orozeumnvaen,oonssar amna an,- sn anaons ano seeceromes conssn oorama, zeuvama an ezaenmaomra u,sezuma, cemma, cerema, sasanma, comrsn a non-ocn - ano anesne-nn anaoemna rnec aeccvonr amnsraon o a encomasses usen aaen sceueo soon recevereamen w annmmoenvenon. s meca reevan wnow,arcuar wn wees o e an-- amunnoscroanoun.aen w cen a emomens,e an-- anaons ano sro ran amnsere em veor usen aaen woaseen envenonuremru ennococomnuasasee accornoenvenon w erevous mon. comrsn a non-ocn s- nv aonumoa aonr usen aaen wos recevn amnsraon o anvenonurer encomassesemrozumaor uesn-nnoman accornoenvenon.e acc en aaen wos recevn amnsraon o a mar,orennvoeneonn evnecnomon. cancer. s meo enas aamssnesse mrenoos oreamen o aaenavneenanose w a eren,sarmaceuca acceae sa, as seecaeenn ane eaecve amoun o a asene an an- anaons ano, wen a comrses a - neorne-n.ocnonaarenn com anaon w ann-arcua arn eamonosm aenns,oe ssam seee scueecrosm co-aemsns ceornes, wn a meca reevrman. wnow, osarma, sn sn o nvouma,emrozuma, ezaenma.n mmoa,sezuma, cemma, cerema, sasanmaorama, zeuvama or sezuma, ezaenremaa,rocuraar emmao, cemreenms,a,e n avnoumoa osr ceemmromazum,aos.arma, zeuvama, ccaormranceuoca oneo amsoesco ons,e cmomnsraonosaeorms anasnv oun accornoenvenon,e accornoe aernmaocneu arecaroovsaeeo arsm, a saarmaarcmeaucecuac caom comososon,on,aramramcaecueucaca a ammnnssraraononoorrmm,, o orr v aarrmmaacceeuuccaao ascaceorm comrsn emmunoconuae oeresennvenon an aeas onen ce eae carrer,uen or excen. armraacneu emcaoomseanes oormseonvreonvoen, ane eas co onroeareeseonsaneve onoensru ancaoovrmeuaeeaneo an eea nvenonen ,n a aon nn eua n env arsera ea rnn mcaocme euacsro aseusc a. accarmaceuca comoson comrsn o eresen comrses aeaswoarm eae carrer.nurer emomens,e comoson eran emome aceuca acceae carrers, suc asoseescreeren. sucuaneous,nranvsen oous,ennrvaeneoanc re oraneraom auscousaareneocrmonorormarenera amnsraon, suc as accea armacaere um c s. ona, aarmaceuca e aa ccr aeruer oc aan era coor om exc nso sse uconns ma as oe sereres zareen osne.n annovren caonn c coannane c sounvece o convenonaurcan aens, oruern aens, as we as auvans, enonaner uens, aens, emusers anuers, ec suc asreservaves, sazers, wen convenona mxn,ra . e maerouce sanarrocesses,ornsance meosorrearn anrumaacneu,cass coovmnos oronso areznnownroncesese asr., seaenor s euxcamroece.uarecsm an e a.eeor anracce onusra armac, , . an eeonve ononanuuraceurre en acnomeassoes, o asr aenam aeno accornoenvenon aove,or usen a meo o manuacur na asec,e use o s as secenea erever aern e o a mecamenorereamen orrevenon o a cancer. seuence, or canacevers areora sn oue seeraerna ase “eemauoresm seuncs” a,s,soro exaem unee,r ansoeroen or con mae comnereeoormscree emomens oenv soo a suc aernaves e aernave emomensor a mae comne w enonscoseeren.us, an o an-- anaons ano an ese comnaons ma an oe aernave emomens o menon e comne w an mecancaon .eooe rwoxner m eemn. acovmaens are encomasse envenon: - an an-e a cnoone ane comrsn: eav can varaeomannn-n,o amna an caa caen onno -, comrsn a - an an-- ano ane varaeoman - • aeav can v nnnoman, comrsn: • a can varaaraeeooman-- an a man-- - ann- oe e aeas encao : v w a serene-oees covaenneoe--, ore--,orove.e ancceor connuoou esm reocommennan, woeee. comrses: rene an-- ano anennnoman - an--: com,rasrncu, oar conssn o aoee aeas encaoe seuence : as aeras w oenree an saoee aeas encaoe seuence comareoe seuence mno ac susuonscosenae, orae - an--: com,rasrncu, oarr co wnsesrenn s o: a ao an oeeee a aeeaass eennccaaooee s seeuueennce : as aeas one amno ac s ce co usuonscosenae, orae.em - ce aca ocroe ers nno o soe e se nmu caoen nmceenn o sru,s w: eere.nnn oemrozuma, or nvoumao a.e accorno an one oe emomueennsnon, w oe o sa ce. - een-ca coomres sees aue vnacreaeoman c:om,rsanrc,u oerr a ce ronn wssernen o aeo-e coe aeas a varaeommanr csoems ar mrses - e - co s vanra, oer coonmsasnn co omrsn, or co:nssn an o aoee aeas a varencaoe seuence :,arcuar werene - comrses eas oaneoman comrsn, or conssn o :, or aoeeavn a.e accoer anmnoo ac susuonscosenae comareo :. - e - com anrs oense a o varae eemoommenso, weren eas encaoe seuencean comrsn, or conssn o aoee a comrses a varaeoman comrsn o :,arcuar werene - avn aeas one amno ac susuonr cosnssn o :, or aoee : cosenae comareoe seue encaoomr a nce - e - cesne sse au varaeoman comrsn, or conssn o aoee aeas comrses a varaeomeannce com :,arcuar werene - avn aeas one amno ac susrsn or conssn o :, or aoee :. uonscosenae comareoe seuence. comerses o arcc coorno an one oerecen emomens, werene-oee.es cova acecnors nos as en o o on ae o-eremnr: uesce. on sa em-omeonse, weeren an-ermnus o sa-- wereneeeneras aen oo amno acs. aeener,arcuar v .eremna re asccoure oo s aan on-e ooe eemoem areen esmeo,e w werenn a an com-eremmnean raersue an a- reon oe--,arcuar weren aoee conssn o,seroeermnn o-ermnarecon, aeener oo amno acs, an-oeem-ermna ner oo amno acs,s , an aee .e accoro a emee wn a oe--. covaenn n one oe emomenso, weren an-ermnus o sa--s eeeneeroa a-ermnus o sa-oee aeener,arcuar weren ..nns eoxareess nounce vecc as oc a r c ee onn mco o rsnn aeo a nuce am cccnoor acns.o an one oe emomenso. emomenso uner conro o aro ac encone accorno an one o .e accorno an one oe emmooemre oeraen a mammaan ce. emomen, ore exresson v nso,esoae nucec ac accorno .e acco ecor accorno emomen,or usenrean cancer. we rno an one oe emomenso,or usenrean a canceraen, anreon, saarc cuaanrcer weareenn sas r aence-vn- c aonnacuorrnesn anreaomens s weec an an-- anaons o nvouma,emrozuma,osarma, snma, eromes conssn sasanma, morearcuar we sezuma, cemma, cerema, or nvouma oremrozuma rene an-- anaons anos seecerom .ne an- ac-cor annaoons an.oor usen a canceraen recevn concurrenreamen w . comn an one oe emomenso. a - eaon a mse seccameenn c aonm ornsen o:e emomenso, rnom an-es- co annsasonns o a nnvoouma,,arecmuarorz wumeare,no ssaar amna-- an anaons anos seece cerema, or sasanma, morea , snma,sezuma, cemma, nvouma ore rcuar werene an-- anaons anos seecerom envenonumreror eznucmoma.asseseoownems: m o.ronve e ane--- an, aon anen-nnoman, comrsn aeav can varaeom co amrse cs,a orn c voanrsasse oo am va an - e - anraoeeomaen com-rsn, c, oarra cconesrzsenna: : an o - suesu-on cosmcorssees,n ora coness cso om aa vraeraoeeo smeaune cnocmersn aea:s on.e amno ac v or. cones asns- o a- v aanraoeo amnanen c-omnrnoman accornoem, werene- comrses, ae comareoe seuencesn a:eas.,,, or amno ac susuonsscosenm.rnov - aen-, an- an-zo anen-nnoman comrsn aeav can varaeomanoee - e a- ca cno varaeomanoee -, caracerzena: ac susuonmsrcseoss,e orn conasses o co am vaarreaeooem saenu ceomrsn aeas one amno - e- comrses, or consss o a varaeoma nce : an susuonscosenae c n comrsn aeas one amno ac .n ano comrsn aeas one a omareoe seuence :. one oeemso. n-- ano anennnoman as secen an . -roxme an a-cva-e an coon aenen- comrsn: - nnoman as secenem -, - a anu amnan cone, an weren-ceo anne-c anoone a annoen- annnen-onmann caomaane c oomnrsno sauman cone, varaeomanoeecone-, an a es an anoeav can o n ano can varaeoman an wereenee ccoone-, cone ano anennesn convaenomann aesaor oe a c sonnee- con, ourouse r cecoomne- oe an- ca nanoee .en. - a acrcso arnnooeemav, a wneren ceaneesro ameeerroeramerc, comrsn nnoman as secenem, comrsne an-- ano anen- - a an seceonn-n anoeav an can oreer aonmer comrsne an-cone ano .n an-- annoo amnane. oee- n-nnoman, comrsn aeav can varaeoman - e---, an co amrse cs,a onr c voanrsases oom aa vanraoeeomaeno--e, ce caracerzena: one amno ac susuonscosenae, or omrsn aeas : a comareoe seuence - onee am-n-n o a comrses, or consss o a varaeomanoee comrsn aeas :.c susuonscosenae, or comareoe seuence v o.ee ane- co-vae annone anoeen-n-n, ooman accornoem,urer comrsn an- o re-- oe an-- ano anen-nn.maenoro avcceor a sne conuous recomnanoee can. comrses noem or, werene an-cone ano anen-nnoman . c,o omr consss oe an-- ano anen-nnomans as secenem or. - a cenr asnn:o anen-nnoman seccor a moecue exresse one surace o a - - a ann an-- w-o o seare ae nn a snaoe a an ---ne anon- oenn aneso en cmoa -van ne ans se nonc mee anon oeem rov-. e- a s,n ore ceon-u-o emomensn ans au rerco vanemrn aeua ssn us enveno craaneoee erawne.oown exames an ures,rom wcurer nooms scoe. .ese exames are meanousraeenvenonu es -.cr sonoew oseures s.ecomnanos moourseao-nrme- an- umse- asa corneroe com-ounn m.ouse- an - comareo rm-.an ooenc on- ces. n= me *oenc aenuaon o mceearn s.c. umors.ce we an-.umor voume overme aunsonaro.en oro asne u enscaaraee anouseo-rer oenaea.v. wumo vre vocume,e aeve arna-em--mm-3s.c. umorearn mocne. suom uosunn ore v aenc-me we-rene-ceu osnonarsoenu amsorre vaomumene aenn -mm3ana.e conro anoaren m- was use as conr averae voume overme o mceearn s.c. umors. oreamen.umor m- -usonroen. m,.v.,- ce werereae.v. w vece, an- eworeamens ona umor voum ocn m3m,.. ore comnaon o comer anassr+e averae+-mm ana.+u+anca-on oo+w s.c.umorearnanzme mrcze we arnerorn cooxcs - - . - or vece wenumor sze reaereae wm an-m3-aree-αm- aer.v. comou ce an averae sze o mm.s were anaze ona .. s soowwsensnne acorona.cor aroxm acvae cone. ron s srucure oneraconeween- re, ron ane -varre, o.e-ermn amno ac o -v aneav can are sown as seres.: areren, o rnoenra.coneween- re, ron ane-α an- : , v .- snows noone-coemr we avernn o -z-me or r o recomnanuman rs -z-me oroveocrn we-rearuseen a onoesemrozuma orvouma. e surace was aceve.n a secon se a mxuver a- coae c un sauraon o concenraonoeer we arove -aren arne ooese wncae ano a sauran . sows non-comevenn o asuse. oeer -z-m or o recomnanuman-n -c anus we ovuemr aan-- c.oae s-z-m or wereremxe w recomnan- oane. e maxmum resonse nurace.nn oeorme --c-ano comex was ano comex was cacuae. reaorvmazeoe caureeve o--s o eac --c- . sows comouns w ereen res vaoennsce oor e ceuasu comeon w -. cone ar memrane anenaren moeo -.:-m. comoun- onra snusenca msce a,nearnnravenou ss.c.u.m soorsw, werereae w vece ormean- , n=.:umorrownon comareoreasm se.c. umorrow overme o we cane overme n w vece..ows .: - anass omea cnom-oun,n n=. or muaons .a cun w ew-,- weee an ro c oe - es sows oneaneoreaer, eeon uonwner rearuacnra cosnroovnse an non-reucn conons . ese are no meanom exemaroena avanaes oe consrucsroveeren. or emom nerenscoseecnca eecs oenvenonn an os asecs eencs. we c wonscrucesar a nosve eraecs: c,.eer.en m-a anresenem-rov reecenorsn. ors a mna reos euenr omroev ceeuaerraares ecac.ernnn moees, comareoose oeror ar, ma oer a neweaur euc a newaree eoe, wc ma oer an aernaveoraens wo nooner e, suc asreamen.eraon maeo varous caracerscs oe , su resono a curren caneaoeer an moreocuseumorene c as sze, srucure, an care, osruon.eraons maeaomrovearrmaaon, wc resunmrove secc an ssuesruon, resunn convenenc conecs, meannonera-e aneer an, sorera-e oe oenveen oon u cse an mnmzne eecveosae.ne oer anereore se eecs.nm an reuceeuraon o ssemcmmune resonses e oenvenon ma zn an-ru ano resonses ma asoe aceve.urermore, an maeao snersceeer sueor amnsraonn comnaon w aonaeraes, oee exenae s e oece.nvenonresen reuceoxc anmrovearmaconec re meaeeraeese,r a ssu waee asorn u azearnoanven coosmnn s,a raouones r.emeens ws ac ocorern ceocoennvnenonor msa or v e omraooreeren mecansm o acon, aownor moreeneca cnca oucomes anersonaze e e cce onnra scraes. ucso oecneoonvcea asecs: uanes.mzeroeresnon mae easer an more cos-eecveoroucenare urcaon comex anmr, suc asos-ransaona mocaon, sou an sa, reuce e consrucs oenvoveac conssenc,eanomrovemen o manuacurne. roues o amnsraon.erenon ma oerreaerex normuaon, aownoreren armaconecs. ereramaon oea-eexene or sorene can assso mouaeoscs an sorae oenar aonuc c.emeca usa sae o a oe s oenvenon can sm avanaenssueeneraon an canoenao noramens or nanooes can oer ocusn on cos-eecveroucon or saeorwer coss as we asmmunoenc. sueor usenow-resource sens. muaons, a oenvenon coueeer xames xaemnveen:orsar coennrme-e snrancneoa- a eexnuressn ces mnmznoena averse evensn a mouse mae- can mananeraeucenes we anouseouman- -.e mouseoe- o a cnancoer u ussne an an-mouse-m-acn ceconnor acv.e-as an aroxmae was- ao nono-wanaonsc cone mouse- receor comareo mouse-.e an-mouse-usonroeneor anore a sroner- snann-+cesro -nuce o - m mouse senocesmeasure eecnarseeoreaveer anocaze acvaanonn- cesure.e comouns a moeorumorrownonn mceearn s.c. o-u.maorrsen c oome-o- ceseaooenoreamen w vece or non--aree ano--usone rreoseonses,. comareusonroen sowe aose-eenen anumora resonsene s.c.n.e an-m- - conro an-- ano sowe on moeraeumorrownon comare moo vuse moe.e ..e comnaonreamen ecereamen roe o a suomaose.m o an-m- -uson aenns o wn a mouusmeor-rowocnn ano m ..eo a sron snersc eec oewo ure mcea were re-caeneo wn, comeareo vece an eac oe sne aens.. creaomoxencnsuce a+n--u+mor-m-mune me+m aosr w.e ae cene reeceeumor,n s nuemr eexr oressroannzevme rz+ca annearorne+ncrease uonreamen w αm--,ncan enance cooxecs orz anerorn was veneromsnrecncaaa oane w e surroae comou ene,c worucncons . eecveareeever o aenuae-o- exressn ces an sncan an-eumonsraen a mouse moe,eocus oeresennvenon ssoeeveomen o aumamor acv envenors ameorove- snan secca an saeoare cesne mraeaenus oc. v arrmoxmarencv aa cee meomnreane an ceonmeo.un.,s.-es aen comeo suencons ar aesecc anoes w oneusonroen.e cone armncues an an rmen an ano-cone nn se, omzeooc ssemc coo seccannoe cone as receor secc anosounoe ce memrane anne sennan. w.eermn snan wene oxaumr ane:encaon o an--nn anoesocn-α ocers w-euremanen-ea-e. ann aorse esxearm weenre,eescnrne o as eac- an recoeoor r aecomana-nα- acrore- an,ovcaa.ee ooen-aeα r was- as-secs-seva sucrraoceosassmemons re wsaosnance anass , cnoaense wc,ere use as aeorws r aane caure on a a a oe,umeon aroxm raunennue.raen aenc- a- aowum ran mn w s assocaon an sssocaon.er sne ccenec a er ae o ,,,. an. n e recomnan-α-cr-α,cro en concenraons secon anaeue a nn uer.eeneraon ossems was use ase a, aow rae mn.ne ccenec wa os caerr re- ou wα-cw mea sen ase an-- anoes , same :nommoze r , an sowe nn an oserve a -.ernecon oe secon anae, r-α-c, nonn was wasoce.ersseocaon o oe r-,α or ,ncanann oe-αo- no -c was oserve aer w a conro anoaoes aneno none-- a-. n aon-cooes,ne co amnexes se wuences s,owen anno r- was oser.veo-α. nanmeo ource rmnm-onzeonocαn-e o r- cone : :es oc con... con.e e.. : :es es :: ::eess ees cone s eunconoas neourraazoano onn eucraca o cese a aner- smu aanoes oae wasese anasnncreasn concenraons o an- a on w r- aone orn comex w meum conan noes.ura ces werere-smuae overnnrow uon seres san. moro--mrsae--aceae an. monomcn. concenraon or.n n a r- nn o cee c aunu-re m-eu amnoores m wnausesre.aurrea a cnesn wceurea weas wxe w eoreen smuaeor mnues w ano-r- comexes.oseowce osve ces wereeece ow comer.esa werencuae wr rae- v er wcenoaue oocn an coeess w waesre re aucreox umaonere- comareo unsmuae ces.e . reucee cesoess comexn o r- we anoes oae a concenraonse an a concenraonserann an wneracon w -rα anan ex. ne unaseec.conwenver,oee a rencomonan-α nnoo socown a-n neausr naoza suona aenoroceeveomen o a .e ano soweoen- snan aeercena ae oe-αnn. anoes e ura ces aer smuaon w r-re-comexe w an-- cnonnceonraon .. . .. . .. . .. .. .. . . . . . . . . . . . . . . . . . . .. .. .. . . . . . . . . . . e.rsa sruc . . . . xam . e -a ure o an comex w r-ncuaeor a an °e.uem caonmneerxe wuasn-ure- s azne eexncu were mxe a:. moar rao an n .rsas oea-- comex we son cromaora uerex o. mmn. ou re oanen snro a aroen concenrae were coece on m maonae ., wv ,.wo-- aa ses sn e same crsa usn aer eecor oneamne aamon comcrnoeron ann secxaee an usnnerae usner au.omareevouseonwe r _ .eaa ses were moe was useore mo esouon. crsa srucure,our ecuar reacemenn . unue souon wasoun w usn coesne asmmer.c uen.eree mncoee ee wcarsonveenns c mcaes c oaeo renemen weaa examneor movemen o anoos or se cans.eoos werecueaeno aeer enecaro rnenemen was an rene usn .aer moecues wereen a ens usn acemen oonn an rene usn .e sruc e usne waer roen moe was cece usn avs e uraeomer oena srucure o-ouno as a., an cece usnaesro.e - comexeser asmmerc unee.n sovoeur c aom.exes resaovueone sam.e-. :ere areour- v renvoonvsenner-ace.nenne orac-onner.ace.nvovesex nvoven-αnn an oxameneera.earao cnom oounnns w an a or o r- mauraon oa rane o an oe an-- ano, an ane- reo ons. mua wnass oerorme werreouenerearmene maucmuaon an aanne susuonne e cosesermne an amno acsa wereerenrom -, - senuenecesra oe can -, - an oeeav can susuon oe amno acs omeweor re reonosns an an reemova o a anosran.sn aon, aanne sene - , or enerae aona muanaona mocaon varans were exresse asaramensn c s.ese urcaon a es.ur anroenroucone aerroen eeacnarenr .nnee re -cusor m oen aneae. cac msuonan wso r- was assesse acore, eacare usn x- asmmoze on an amne reacve c croossems were caure a ruonwn rnaeuermn w ea s cocnaraec.mee.comnana a-n-c muanas were run as anaes,uenx- runnn e s assocaon an sssocaon aow uer eacare w m cne-, ..e assocaon consan raea,ssmocna.oen reaneer caonosn was carre ou w ssocaon consan are reorena an an eurum aneecs. ou erac a cnoneeD me aaseurrroen o e. cone muans exresse asaramens.nn ,e r e . *edvaueseonemaon oensrumen.- measuremeesnu.sere sowe <.-or reerence on. was esmae usn onea cnon-e- uaon ur ea d D#w - - . m. .s <s m . .-* <.- m . . . .- .- m . . . .- .- m . . . .- .- m . . . .- .- m . . . .- .- m . .. .. <..--* <..- m . . . .- . - m . . . .- .- mm . m . . .. ..-- .- .-- m . . . .. .. ..-- ..-- v mm . . .. <..- .- m . . . <.--** < <.- m . . . . .- m .. . - .- mm . .. .. ..-- ..-- m . . . m . . . ..-- ..-- m . . .. ..-- .- m . . on .- m . . m .. . . . . n.- .- m . . .. . .- .- . <..--* <..-- omnne muaons oe cone.s w moe.raeecrea.se a .- .- anur aer one seurcaon w aona varanso renmov aenooeonaroousc-rvae mocaon ses, anor remova o rare occurrn resues-, occursn oernsaon - ,- ,- , remova o-cosaon se mnevs. o roocac - , occursn ar - an- remova seuences - an no sncanmaroxnmane o cone m occurs-n , o occeursermne an occursn oeermne seuences ness o cone m resuen a - an no sncanmarnn necs oe muanso rona- co wneass, a esxsersessese asaramensae.enn ,va was useore acore ,va.s-caure -,cam was are as-caure c ,va. r--s reace.erauons o caurae a anowe rae mmuna unna as ca weurreeve o - was x runnnuer ,ane e run as anaes,uen sso c as sne ccenec w s assocaon an s assoccaaoonn c aonsoawn rae mn.eeneraon was carre ou w m cne-, ..e re a,ssocaon rae consan an eurumssocaon consanD are aoerenssoae. D o mnua-nc vaa-roann cosn osana,ssocaon rae consan an eurumssocaon consan uaon co.ma:r noeermnae cone eo w:w .a.d D, , , , - .- : : . .- .- v ,,:, , , . .- .- , , , : : , : . .- .- , , ,: , . .- , : .- , , , , ,:, , : . .- .- : , : . .- .- ,,:, , , . .- .- , ,, , ,: , . .- . , : : - , , , , : , , , : . .- .- : ,, : : .. ..-- ..- , : - u,: ,erm,nea,:, . .- .- c mua, . .- .- ree aona cone on n n n muaeness s , , wereesne crsa srucureueo r- was an ass eexssreesse asaarcaormeens,aeva..se canurnenecs oe, muansoreare as-caure c ,va. r--s - va was use caure aow rae mn un a caureeve o ,cam was a ane muanas were - was reace.erauons o ,anec as sn run as anaes,uenx runnnuer mn.eeneraon waes c cacrree onue wc w m s ascsnoec-aon, an..e sssocaon aow rae ssocaon rae consan an eurumssocaon consanDare r aessoorceaonn caonsean.a, v e a cnomooeusnse.scree onmzsa eoxnam oe we an varon's a annoorr c moasnen-e c weroe unzeoenerae comoun can enance seecvowars- exressn ces. e wne ese anoes ensurea cone snansreomn ne-unnenn an, maxmzneraeuc ecac an mnmzn o-are-cean ee accsv.aenearee ces,ere xaemnve.mzaon o an-- coneor- ,en vaorraseeveooewo an-- ano cones varaeoman : :, varameaonman :: an.ese-z-meav can varaeoman exsn ceconnors ae.e ma aen uoeso nonerere w enn o everne- snarecoe arorae-se as caren moeesn an- ,or oma comnaon w exsn an--erae es.sareeever aows aree- snano- exressn ceucs.e resun comounsrove curren reamen remens. s an oerreaerex n comnaon weos ceonnrmrae anoes an -z-m are comnae w s,nn was ura-es eexncrees osn sa cuerasn we creoncnecnuraaeons o menmuerso azum°a w an nvoum oaeow comer. nvouma. ou wasne ces anoes an -z-mamereozuma an uor were ae a axe concenraon o n. eves ooun com w exa comareo n sames wou comeoroeermnee snan oun were mnma, uner , sown neeremrozuma nor nvo on.non was o uma sncanecreasee sna a aneo.eosmeo an -z-mae. exresse on ces wn o co amno cones an -z-m asuman on - snanon oeesmeer acnao- u asnnaonxs mso,arem excreosszu om caom ane novrouma.ow comer cnon-e- ano cnanonn w x moar excess -z-m ee .mcrooznumnaor an no .vouma . . anmuaen aesosuoscanonn o oeme arnozoumeas oor nv-ou wmasa co wnrme ure.- wasmmoze or as assesse, aernn o cone conveeno-z s en rs- cmoren. -rme smar reenon o-nn acv o consrucs comrsn a s ncuae wemrozuma,vouma,emma,osarma,euvama, exceuzeuma,esznae cnromssa-rea ocrvor wamaeneoro senowxn.e-caroraerrananorm o.o anoes was v arans-z o-m,u no an ,- sz-mner weerrees wenerae- asnennv,e anso srsow asnsae varure.ne seuence w vewooenaurermroveme ous canes caracerscs, manuacur nsnarameers suc asnn aens aneeaea an, saae s, soawe su,sranusoenrasa w oer aen amae sune resus reoounmsa onr seecoann on ree amonnso o ace s oursnauon was cr asna srucure-z-ume an anaoes, resecve.e smar, sze oe amno ac se can, ex se onscocemca as we asowr cuson ooena new ueo neorn resues, coaumen anaranese m oc ua aenon-mm com-un a ao rnen eoc o c rs eonn.ecaearen.ae senueernc aens. muaon aresenee nanm-e- cone uaon : - : - - - - - - - - - coaumen anaranes m ou aano-n co-m anareoo coenencae-azre-nma. seenuenecre asn. muaon aresenee n-- cone name uaon -z-m : : v ne an coes. vanraoeeosm waens were exresse asuman anoesransenene exresson suernaan, as we aser aenurure aroemrreoe sunernaan usnroen.xressonevesne aerouc arameers oa are reorenae anae. arens an v rena cone an oe varans asuman . anoesnaera snuernaa ann woasesee wremrenerouce un m ce cuures.e concenraon o seurcaon wroene concenraon was msenasureao,r an we a ovreoraen sanar.er sne oe comouns waseermne - an- a an nem. cacuae.ur omoun maornomncemnraoemur- u- . . > r . . > . . . > . . . > . . . > . . . > . . . > . . . > . . . > . . . > . . . > .. uamean.ro.uceemarmaumnezeers v oaraanresnas were-zr-omuc ceonen an m oen cceae cu vuarreasn.s aes v c soannceanrra.oner o sn ane soeesunrcaeo sun wernaarone wnaseee cromncnee usnaor w aroen e cacuae.ur oe com nraon was measure, ane overa nm. ouns waseermne - an- a an - - --... >. . >.. . . > . . . > . . .. > . . . > > . . . > .. .. . > . . .. > . . . > > . .. . > .. . .. > > .. ennacnoerecs o,e anva-.-n a-numoanesoucman avna cunroomeoums mon we- was assesse amne reacve c anecoanacsm usnx ruansmmoze on an oanacsm.e um anoes comouns were cau nnueranec s.e anensuman an cnomous- - aren a aow rae o mnor croossems wereuenx runnnueraneco - , resecve assocaon an sssocaon aow rae mn.eener anacsm w s cne-, .or s an .or s.e assaocoano was carre ou w m rae consan an eurumssoca2on n consana,ssocaon ae necdnnarameers consanDare reorenae anae. cnomous-. oarena cone an varan comounsouman an v cnon-e- nnsoumans- nno cnomous mone - .a .d- D asdsD... .. .. .-. .- .- .- .-.-.- .- . ..-- ..--- ... ...-- ..--. .. .-- ..-- .. ..-- ...---. ...-- ..-- .. ..-- ..--aane cnomnoeucs.n-n.ar =am noe.erns--on.arena..co--ne..-z-m an va..ran--comoun..so--uman n---zc-mone.annsou .dman -s- .D- annso cnodmosus monDe - ... .. .. .-. .-- .- ..-.- .- .- . .. .. .-.- ..--.-- ...---. .. .. .-. .- ..-- .. ..-- ..--. .--- ...-- .. ..-- ..--. .. .. .-.-.- .- .-- .-.- ..-- .- ....--..-- ... ..-.-- .- ..-.--neroc.u cma - xaemrener..esn o comouns cone a srmra oeeesous ceom- : oe an-- anooreneraon oe seecv on- c ouns, were assessen orerone comouns wees eav ca es.usonroens o--ermnusoe anoes’-ermnus one anon or ca can wereenerae.n aon,- was emeene reons oe o-.neonown o seenne ee can anusne oen ensoe- an-ermn comouns. conse cone armuson sraees weescreor varous v snanaaernsre reacevn - ceconnor era w a- anaons ano, now a roenss armeenor man cancers,e eoearee ocn -aree coneuson ocn an-a- oacrcuene anoee eraeuc.us, exsn -aree cones usn sanar ceconnonreamens reavmeerawac oenncomae as an aunco comouns,e an-- ano conees.n ars se o emomens, asaren arm oe varaeoman :, s : eav can comrsn was us : can comrsn varaeoman : oroncoe.ac comoun comrse an an-- arm covaen assocae va an c eeroeranmsearncourma, weren eer: w an an-- anon asecc ano, oee.ewoeren s oee a onr-e- a oneo an a-n- aen ano--sn aeo an- enneereoorm aeeromernsernnos-no-oe muaonsnos: ,no were , , , , numern.orrec asse oes: aceve wou enn m oe resecves was an oneamaan-ee-rn oe na curoan seuences, usn oneaa an-- ano conansc sencn muaons , e, canec numoreornn oesecc comouns arm wasrovease on varaeomans o varn a .n varous emomens, an- acone o a ano n aes an nserenoe :,, or was covaen: as, : .n-oee arranemens asescreneaeow.masrocae co wnsr eere ore vanae varans oe-oee : comrsn aucesas co oune c moumarse muens o-, varans comrsneeons,nserons, or excanesrom o on, or cmerc- onensaar .narcuar emomens,e comresresro anens-,eo- en , seeceromerou conssn o :, an . ee seuence neavo ceanusonroen roensso- on,e ano,es’ea,v can.,e an were useoeneraeusonoe-ermnus o- roueeners.a-rearnmsnus oeeav can wasrecuse ano an wereenerae assenae.e senecnver oenn-,e cxe an an-- a ceuar assa usnura- exressn ces.ura ces were s was assessen meum conann. m an. monomcn.urare-s-mu caees w oevernnrow w .a oe ces werencuaeor mnues wearena an--re a wnasoe cwonce ,n orerooce -nn se one ces.o e oce ces wereen s e-oce ane non- ces wereeecemuaeow corome mrn.ues w auon seres oe comouns. or non-oce ura- ces wase cacua oeeon comeo cuonnces onoceBces.eNoB-erencenoenc onoce vs. non-oceunrraaon- a canse cacuae v es was vaon.ae,sen ecncn- oBw co-mrαsnoNB.e com cooumnosu wnesre w caas ausreses osne auman anaocore caure, v c seraauneocn, o-αcrova,ossems, a-ow rae wa os usem as aona aeroxmae - . ueranec a aow rae o mn w s ass ,uen runnn anass wase ocaon an s ossocaon. mu cce recomnan-rorαm.ee usenneraone wraesn c caorrnecen oruaons ,,,, an n oe =. aow raes o mn.e sna wa w 2 a=. an cne- a eorecamax w s consereosveornn wen oe an resonsas aceve, cacuae woownorm n: ua m ax: m a xm a sna,: caureo anaeeree-ereαcom: moouencusa,r w:eocoomear o caure an, : mo:ecuar we eav co cmaonu wnesreeaeurn a cone arm w-useoe-ermnus oe an-- ano comounssennaeraee u esxn v eanrnancenerose anncnneren an-- ano varans. accesseornn,ncan eecve masn oe-u rcenceornn s snaenn a w noenn-ce-o was sae, an eecve unmasn anoen- rernne un ae. comouns w an-- ano v are ceoun sae. - ano cone was use.oencanrannusc, wn naoes.oorr aa coonnsnrucusrae an- c aevesraeoc oe n= exeBrmnoenn-so *acveerae o nNB,eerence annn oe r-α .-#ese osvease on cacuaon,o=we evxere srumeencs.anarevaonnareness. = no nn. ve revew o sensorramsoes noncae naommeoun ann-o- n-erooenc onura- ces co-ncenαraon an nn nNBnB r- ..*..*.* noeseseses .. . . . .. n n n n n . . . n n n n n .* .* .* n no n no n n n . . . no noes ..* ..* .* no no no no no .* . . . .* ..* no no noeses v ..#..#..#n n n n n ..#..#..#n n n n n n .. n n n n .#.. .#..#n n n n n .. .. .. . nes nes nes nes nes canusonro rnoeonseso- on,ens, m, , an were useoeneraeuson e-ermnu e anoes’ can.e-ermnus oe can wasrecuseo se s o- roueeners.arans oe an-- ano wereenerae as -n cae.e seecvor- ces was evauae assessn cesnura a-ees, as ano c coomrev neoouunss wescr a wne a-. s u-se a.nooenc vanranns, w nae.or a consrucse an- cesoce non-oce ,eerenuccen annons ooraonnura- averae o oBr* exermens.NaBnarevaonnaren e r-α . ase on cacuaon,owever suecve r ess. n = noese osve omoun n-- n oencev onew o sensorramoes noncaenn. name ano er- ura- ces-αnn a concenraon eonNBnB n r-.. . . noes es es es . . .......* ...* n no n no n no n no es ....*.**.. ..* ...* n n n n n n ....* . .. ..* n .. n no n o n no n o n n n noo n noo no m ..* ..* . es m . . ..* n n n n n v m ...* . ....* ...* n no n no n no n no n ..** .. ..** .. ..** n n n n n no ..* ..* .. n n n n n ..* ..* .* n n n n n .. ....*..* ...** n no n no nes nes nes .*.. ..* .. . ..* n no n no n no n no nes - was co amcceosusnseosrennna,neca enx ee ecnvean mcaesnoe oncenn-uc renceorn snan wen ceoun sae, an eecve unmasn anoen- rernneare ceno sunen s aa neo.n- masee a oe nnne-e crrms- naus srucure o o-e ano--e amano ac-s conmeex,esancesrome-ermnus measureae.e am - reon oe ano were cone an ano were seneo acs cosesooermn o-ne non-covaen assocae was ceaveeweene -ce resoru eemse ann-, w as nnume ano.e ano can aren seuencen varan anoes.e-ermnus o-ere com waasreuseooee : can a rou cne-serneners o va ano wasuseoe rousen, ane-ermnus o- e-ermnus. ansroocess e can a , usn acne-sernener oe sameen use a sns srae,- was eemcveee emneee an-o wesne,- se,uence ome, ano. an .e seecvor- ces was evauae a , - ces, asrevouse ssessn cesnura asse screae.nn oe-αoe use- was aessesance, a ose-scroe aove a. e emen o-. mno acsn. an oe - were cosenor a- -- .er -er . . . . .. .. . .. v .. . . . . . . .. ana-e- an coom uosunns va wrou vsarnouesr an-- ano varans an- emeen - o#- cesoce non- ens.oencnnucn osoraonnura ..anar avereavea oon enxBearoce NB,eerence annn oe r-α rmeneness, osr. * n e =x neormeenses.orosvee vaues arerom exermen suwecve revew o sens ase on cacuaon,owever o orramoes noncaennneavease on cacuaon, oemveoru suec annv-e r o-evew o ern s -o anen-sororaemncoe osncaenn. n name nura- ces-α nn a on-nNB Bconcenraonn r- .. n. . nosesesees . . .. .. .. no no no no no .* .* n n n n n .. . ..* .* .* .* n n n n n . . . ..* ..* ..* n n n n n n m .. .. .. o no no no no m ..* ..* *.. n n n n n .* ..* *. no no noees n n ns m .* .* .* n n m .. . . .* ..* .* n n n n n . . .. n n n n n .. .. . . . no no nose&es v . ..* ..* *.. n n n n n .* . . .* * . *.. n n n n n .* .* . n n n n n . . . .. . no nosesees ..* ..* ..* n n n n n .* .* *. no noseees nonn- . . . s n c er .#.#.#o no nose&es&- wasomounssenae ex enanceoencnnucn snan wen ceoun a scacees,s ane eorecnven un,mnascann a enecoveen ma-sn oreern-n receearore cneno sunen s aa neo.n- m erme manre us, emne ann- o-er-mnunse - o w-aserroourmen ae coses resuesae oe- reaveo :.usonroens w- emseroneween an numere e an- anoes , , m,e aenne w- weerreenennerae usn e seecvor- ces was evauae assessn cesnu erens. revousescreae.nn oe-αoe use- warsa a- ces, as asescre aove. ssesse , emaeensance o-o amno acs. an oe - were cosenore - o--. a -er -er .. . . . . . . . . . . . . . . . aeos coormaoounn. n wura-- em ceeseocne-B on aonn--o-ce ano.NBoanencnnnn oucne v r va-ues aαrerom. exerm aevnerae. oan oarr*ev eaxoenrmnenasr.or , an e on cacuaon,owever suecve revew o sensoreranmesose.s n n = noese osvease ase on cacuaon,owever suecve revew o sensorramoeosnnccaaeennnnneave ame an-ne n- nura- ces r- on- r-o an-o -- -nNB Bco-ncenα. oenc oranonnna...n. . noes ner. #. eseses o .#. .#es es es es es.*..* *no no noe&se&s .. .. .no no no no no..* ..*..*no no no es es..*.* .* . ..no no no es es. ....no no es es esm..*.* * ..*n n n n nm..*.* ..* .n n n n nm..** ..* .*n n n n nm...** ..* .*n n n n n.. ....n no n no n n n..* ..* ..*n no es esnnone-r ..#..# ,.#no nno nnonesne&s v usumsnoene nreoren sn osn w- creas-n eemnes,eeweene - amno acs an wereeneraeoe- was ass rannromo amno acsae.nn oe-α ae comouness wse one an,- as-escre aove. an-- ano rou varo ano varan an- emeen - oe was usners.or a consrucse an-- ano cone oc uese.oenc,nenuecrennce anosnoraonnura- cesoceBnon- ex NB n oe r-α . verae o aemremens, orn * -- exer onme -enrs.oanenacr onevuaraonn-ar ceensess-.αnn a concenraon r- .N n nB . n.B . . no eses es es ... .. .. . no no no es es .. .. .. no no es es es .* ..* ..* no no no es es e csonsr-uc–sencororan-noe - reon o an–- anoesemonsraee suc as e annen seec.venseu mroaecues ma asnsaanse, w su- vaues exceen n consrucs we remann aenuaene asence oare enaemnaenno,m coomaraoreenco re ocnom-n⁺ ces . an- caneuso-ns eem..,en wa,s mos e,ecve, anonae s reoeec ovu wsaos oserven - an ano annunn acv. nooo,neresn, annxamesee em: :osm weenasv,- ca-oc n vaorcn an an anooeses suc as zmerema can varaeoman : werencoreoroamean asearen: a an -z-m : were comne w cone rm osecc consrucs.ese emeene -oo o armseerverom an ae,eaurn- secc assem was aceve u asnn–n-os a-nno. , , , oreoe, nuom-oeersn m.uaoons , oreno comnn aaa can one rrec canarn was ensure an , or anro an–- arm w aama can one an–- arm consrucs wereeseor-–sseeaneencn soeeocvo ursencroeeurr caan as-sem assa.. v asanecae. comouns w varous-ocn ms an- ano-uson moees n-- ann-o- e- nero oenc onura- ces ame mee - n n zm-z-m - . . zmeerreemmaa -- .. .. nowa reuncee-–-eaerneenn s aermecovro ocrmna arn soseemsc su acen ausa zomerema or -z-m consrucs reane sron masnne asen n oe- cone.e -nn.esee re csuecs ce o- enaemen anoen unmasn uon arcecureso acev sounonreone aans seec ov ues cnone-eovecrn. anoes wn xa oeem nrecne o va:eenacenc co var v naa enra asn rm ms oa ae use comoonucreasee av eec o eerearen arm ore nn moee n.ncororan varn numers o an-- or an--or more rousser maaeu acso e eencasn aceo sweeercvose, reucn o-are eecs, anne-uneeoencramensscv, anen-nnramensas.so, a ocr oeveeroremreans vae.en.c,a sonees-c,an varae aoes, ec.aren - or- w-uson caneuseo sne-can - or-arenomomers, or- an-are e- or-ermnus o mae oane weseesns neeromers.:,:, an: vaenc woer meoeusanee c won vearaoeen vca,enmcr aoveu arev., an enance on-are seecv, comouns - anoesn rcecures,ncun - -ocn or non-ocn an- ,c nuvonumeamrozuma varaeoman , varaeoman zmerema varaeoman varaeom,an v , varaeoman m varae araeoman , -z- va oman : varaeoman : or nurmaeeoman :, varaeoman : .nese emomens,e nnr aonrma orse.naeo rens ou ann–s- w aenre e avna–ua-e mooees were ssemaca vareo exore: on-–exressn ces, w rer a o seecve acvae- snan aenc mouaon was ace remann masene unoun sae. omans wereuseoee-v oer u-senrmn sn oe a-cna–n v-ar oar aenr–am-en asnsocvess. wenseenn v cramoewneorn.o-e was-ncooroo oraee e ane–r v-a-erm cnaan. or-ermnauson, or emene ae esn o : vaenc varans. ame n-- n-- ano s o moee ocrevnaon an ans-u-se nero eeem- scv - -er ssccvv -z-m - - s -z-m - - scv - - sccv - - scvv - - scv z zmmerema - scv nvoerema - scv nvouumma - scv emroazum - scv emrozumaa -- reeevcouvsor- ces was evauae assessn cesnura- ces, as aeNB,oe eesnccre en. rennceucn annnos ooer ra-onnαura.- cesoce Bnon-oce ame oenc onura- ces . n . . n . . . . . . .. . .. .. v .. . . . . . . .. x ce-ame s, ans. mroaaoen cro ecx o areesss- seucmam co rum enceo om cuen nss an o ncn cuu onman nes m aans ave un ceess,re cmemsu,no coecs,enrc s accornoenvenonreerenarov a eecs. .ocae oe-n e- snao exause ces exressn- e oe assa wasenror smeeoaereenrm anne-ow- ano snraorno ssuseuen amnsraon o means o a comrsn a cea nuence wenevere comouns reneauren aono r-.eresenave osora won on:- or: vae cencsn w verreo.esroezenoresr weoreencnnucn seecve an an- anoes.os ac awe anre-acvae w an- are vaon,a oe ces werencuaeor mnues we cesn.ao an-e--o acneo an conee non-oce,n ce orse wreoreorecaee w --nn se onencreasn concenraons.es we comouns a an anoesorow core sane w an , , , , ,-,ox, anaze ow comerouanmer, aon w ces a.veeea ma orere.oow conm soaunnn, ces were or non-oce - ces was cacuae one s onoce eB ces.eo-NBerencen concenraon aans was cacuae oenc onoce vs. non-oce - ces eoenc o-v snnan wNaBs w sncanBreauec. no oserve w r-,ncanae ceom woeunns- eeacrveen m wansmrzeeve on-ear, an eec snann- neave ces.saree aroac ensur e- reerenanuce- sn esa s accornoenvenon ae oenc oB reresenannare cesa exress-. oce ces or non-aocvee c-essnNBn,ucenrenceos,o nr=aon osromonnors.- omoun ceNBs on - ceBon - rec . s . . . . .. . . . .. v .. . . . . . . .. . . . . . . . .. . .. . .. . . . . . . . .. . . . . .. . .. . .. . .. .. .. . .. . .. . . . . .. . xaeme c.ono vrevcoa an ca-nucmeror m eoceac wa os us-eonv ceosmounsnransenc - - mce comouns.rans aee an-umor ecac o seece6- ces.e enc-- mce werene3c,e s.c.ne r an wx a.n seucmonors c roemacoeun an a avmernasera szoe o-mm comouns were amnsere.v.su measurea w a caer an cacuaen w wasevoernmu.va. oenn su x wa x w.umor. voumumes were erencesn comareo vece a su en aa a or voume ose-nensca erreamen onse were cacuae.n a e comoun aon a s aumnserereoasemse wn wa nsovoen a we. moss, omserve o.rm.ceoerae nuce wasose-eenen wees eec a umorrownon w veceure, n= mceerrou. m, comareoreamen vn a s ceocmonare suo,r meaumene w- vece co wmaso ounsesrv weere w am ans-ere as mese ona sua an. a weaemen onumaorro ow-non comouns s oenece e. r s.-c n=ere mrceeaeer onroua.umor voume averae-mm3. aunmor c aeoamr.nouns v. w- com m-are o c mo omce v.ec ouncee. mreamen rou ece -....... x rxamresseon. oro-ease cea cvoameo ouns-n om czeason resueeenone oro mrumaaoonn o ce secesueo ,onevoovcn c aeravnanee w rne-oman.eavae was maeoeooeweeneces an o emnaesaes,ue-s va an . eeons aeseosonsrans w: muao wnseree.., , :, or roeoc cn, as conrme - ur enerae.ese mocaons aose seec cvonsrourcs-nc eoxrorerassnnuersea ce-s vaaranes reaene.uncona aenuaon on-- ces an nomar seecve cone acv. ,emonsrana sa-enancn muaons ae ann -- oenc onura- ces ame o w . n . n .... .. vne eenc evoesne o: seusecrneceanceseweene seuences sownneresen seccaon anose oreva. rooco accorno sanar.,e seuences sowneren sa werencae: u:nernn areea avss cnea ancc voarrnaoeeoman numern ssem. :: can varaeoman :: eav can varaeoman :: can varaeoman :: eav can varaeoman :: can varaeoman :: eav can varaeoman :: can varaeoman : : v : -z-m : -z-m sac:, re:uar:n---nen n v n muaonsoac , -,-,c sencno: , , oes ac, reuar: n-- ano cone can : maure- seuence s : ano muaonasc:,, reuar: -ne-- c sencn: , , nos

[0002] v : ano : acs - ac:, reuar::-ne---z-m : -z-m acs - : emrozuma varaeoman : emrozuma varaeoman : vouma varaeoman : vouma varaeoman : 44: v43 :43:4: : 42 : : : : : : rooma : rooma : merema : merema : v : : uman -c -ne-- nnoaone: aecu:ar: an-- varaeoman oo: euaa- r ucn:erne-:n ane--euaroe un -- cone varaeomaneuarase uneerrnnee:: a ann---- c coone zmerema varae euarc unerne nerooma varae :: an-- cone m varaeoman. : : v::::: v: ::: :: v::::: v: :::: v : : : VLESGPG LVKPSET:LSLTCTV:SGGSI,SSDYW, , reaveo PSLKSRVTISVDTSRNFSLKL GWIRP PGKGLEWIGYISSSGSTNYN VLESGPG LVKPSET: SS LSLTCTV:VTAAD SGGSI,TAVYY S SDYW,CARSA GWIR,GVADFD P PGKGL,FWGGT EWIGYI rLeVTaVSvSeo VDTSRNFSLKLSSVTAADTAVYYCARS SSSGSTNYNPSLKSRVTIS : : ,AGVAD,FDAWG,GTLVTVSS VLESGPG LVKPSETLSLT reaveo VDTSRNFSLKLSSVTAADTACVTYVYSCGAGRSSIASGSVDTYDWFGDWAIWRGPGPTGLKVGTLVESWSIGYISSSGSTNYNPSLKSRVTIS v VLRENSGFPSGLLKVLKSPSSVETT: ALASDLTTACVTYV: YSCGAGRSSI, ASGSVD, , reaveo VDTS AYDWFGDWFIWRGPGPTGLKVGTLVESWSIGYISYRGSTNYNPSLKSRVTIS VLESGPG LVKPSET:LSLTCTV:SGGSI,SSD, , , reaveo VDTSRNFSLKLSSVTAADTAVYYCARSAGVAYDWFGDWAIWRGPGPTGLKVGTLVESWSIGYISYRGSTNYNPSLKSRVTIS VLENSGFPSGLLKVLKSPSSVETT: ALSLTCTV:SGGSI,SSDY, , reaveo VDTSR WGWIRP PGKGLEWIGYISYRGSTNYNPSLKSRVTIS :ADTAVYYCARSAGVTDFDAWGGTLVTVSS VLESGPG LVKPSETLSLTCTV:SGGSI,SSDY, , , reaveo VDTSRNFSLKLSSVTAA WGWIRP PGKGLEWIGYISYSGSTNYNPSLKSRVTIS :DT AVYY:CARSAG,VADF,DFWGG,TLVT,VSS, reaveo VVDTLSRENSGFPSGLLKVLKSPSSVETTALASDLTTACVTYVYSCGAGRSSIASGSVDAYDWFGDWAIWRGPGPTGLKVGTLVESWSIGYISYSGSTNYNPSLKSRVTIS VLESGPG LVKPSET:LSLTCTV:SGGSI,SSDY, , , reaveo VDTSRNFSLKLSSVTA WGWIRP PGKGLEWIGYISYSGSTNYNPSLKSRVTIS :ADTAVYYCARSAGVTDFDAWGGTLVTVSS VLESGFPSGLLKVLKSPSSVETTALSLTCTV:SGGSI,SSDYW, , reaveo VDTSRN GWIRP PGKGLEWIGYISYRGSTNYNPSLKSRVTIS :ADTAVYY:CARSAGVTDFDWWGGTLVTVSS VLESGPG LVKPSETLSLTCTVSGGSIS rSeDFaWGWvIeRo VDTSRNFSLKLSSVTA P PGKGLEWIGYISSRGSTNYNPSLKRRVTIS :ADTAVYY:CARSA,GVADFDF reWGaGTLVTVSS VLESGPG LVKPSVETTALSLTCTVSGGSISSDYWGWIRPvPeGo VDTSRNFSLKLSS KGLEWIGYISSRGSTNYNPSLKRRVTIS FITLLTTISSSPLSSPVESDAFSAVTGYD:ADTA YRCVTI,VYYCAR ATCRAS rSAGVADFDFWGGTLVTVSS D GeISaSWvLeAWYoHKPGKAPKLLIYVASSLSGVPSRFSGSGSGTD : ,SSFPL,TFGGGT rKVEIK DILTSPSS VSASVGDR eaveo FTLTISSLPEDFATYYCVTIATSCSRAAPSLTGFIGSGSGWTLKAVWEYIKHKPGKAPKLLIYVASSLSGVPSRFSGSGSGTD v DFITLMTTISSSPLSSPVESDAFSAVTGYD: YRCVTIATNC r SRe AAPSa LTGv FIe GSGSo GWTLKAVWEYIKHKPGKAPKLLIYVASSLSGVPSRFSGSGSGTD ::::: : : a : a---- : a-- : a-- : a-- : a a-- : a--- : a--- : : a-- : a-- : varan GGSISSDY :: varan ISSSGST : v vaarraann ISYRGST :: varan ISYSGST GSSRGS : v vaarran T GSSSGST :: varaann GSYRGST GSYS : v vaarraan GST n ARSAGVADFDF ARSAGVADFDA v :: varan ARSAGVTDFDA : v vaarran ARSAGVTDFDW :: varaann ASSFPLT ASSA : var varan PLT ANSAPLT PVSLLKSERSVGTPIGSLVVDKTPSSRENTLFSSLLTCTVSGGSIaSnS oDYWGWIRPPGKGLEWIGYGSSSGSTNYN : : KLS vSVTAADTAVYYCARSAGVADFDFWGGTLVTVSS VVDTLSRENSGFPSGLLKVLKSPSSETLSLTCTVaSrGaGnSI oSSDYWGWIRPPGKGLEWIGYGSSSGSTNYNPSLKSRVTIS :VTAADTAV vYYCARSAGVADFDAWGGTLVTVSS VVDTLSRENSGFPSGLLKVLKSPSSETLSLTCTaVrSaGnGS oISSDYWGWIRPPGKGLEWIGYGSSSGSTNYNPSLKSRVTIS :VTAADTAVYYCARSAGVTDFDAWGGTLVTVSS VVDTLSRENSGFPSGLLKVLKSPSSETLSLTC vTaVrSaGnGS oISSDYWGWIRPPGKGLEWIGYGSYRGSTNYNPSLKSRVTIS :VTAADTAVYYCARSAGVADFDFWGGTLVTVSS VVDTLSRENSGFPSGLLKVLKSPSSETLSLTC vTaVrSaGnGS oISSDYWGWIRPPGKGLEWIGYGSYRGSTNYNPSLKSRVTIS :VTAADTAVYYCARSAGVADFDAWGGTLVTVSS VVDTLSRENSGFPSGLLKVLKSPSSETLSLTCTVSG vGaSrIaSnS oDYWGWIRPPGKGLEWIGYGSYRGSTNYNPSLKSRVTIS :VTAADTAVYYCARSAGVTDFDAWGGTLVTVSS VVDTLSRENSGFPSGLLKVLKSPSSVETTALASDLTTAC v VTa YVr YSa CGn AGRS o SIASGSVDAYDWFGDWFIWRGPGPTGLKVGTLVESWSIGYGSYSGSTNYNPSLKSRVTIS VVDTLSRENSGFPSGLLKVLKSP: SSVETTALASDLTTAC v VTa YVr YSa CGn AGRS o SIASGSVDAYDWFGDWAIWRGPGPTGLKVGTLVESWSIGYGSYSGSTNYNPSLKSRVTIS VVDTLSRENSGFPSGLLKVLKSP: SSVETTALASDLTTAC v VTa YVr YSa CGn AGRS o SIASGSVDTYDWFGDWAIWRGPGPTGLKVGTLVESWSIGYGSYSGSTNYNPSLKSRVTIS VVDTLSRENSGFPSGLLKVLKSP: SSVETTALASDLTTAC v VTa YVr YSa CGn AGRS o SIASGSVDTYDWFGDWWIWRGPGPTGLKVGTLVESWSIGYGSYRGSTNYNPSLKSRVTIS v VVDTLSRENSGFPSGLLKVLKSP: SSVETTALASDLTTAC v VTa YVr YSa CGn AGRS o SIS SDFWGWIRPPGKGLEWIGYGSSRGSTNYNPSLKRRVTIS : varan oAGVADFDFWGGTLVTVSS VVDTLSRENSGFPSGLLKVLKSPSSETLSLTCTVSGGSISSDYWGWIRPPGKGLEWIGYGSSRGSTNYNPSLKRRVTIS :VTAADTAV vYaYrCaAnRS oAGVADFDFWGGTLVTVSS : maure- seuence,roease ressan : maure- seuence,roease ressan , : maure- seuence,roease ressan , a:e ceanresen:aevaev c-an consrucs :: :: :: : : : : : : : : : : : :: :: : : : : : : : : : : : : : : : : : : : :: :: :: v :: :: :: : : : : :n an oe aove consrucs oae, : mae excaneor :. een re.,e ere an.ces: awves, e a. e., a. ucreonc.m ocmsunoes.. :e.erverssue: -. ercan,.., e a. o. :-. en, e a. aoecno. :-. en, e a. esos.::--. onnsecnsa,a er a.. roeonnem.es.e. :-. ree srcenecnecereun.caons anaenocumen:s ce-n.eresen seccaon arencororae

Claims

vams -. a anr n aonxm a- ac c aanva n vee an c rnonneoman, c coommrrssnn: aeav can varaeoman -, - an an-- a aeoman - • aeavn ceann vanraneooman, comrsn: • a can var man-- an an aeoman-- - w anere-neo-eoe aeeases covaeenncanoe : .e accorno cam, werene oe-- oroe--. - an-- c an-- ano anennnoman comrses: an , aomrsn a seeceromerou conssn o : ,,n,, a an seeceromerou conssn o :,, :,,, an an an a seeceromerou conssn o - an- s-eec ceomrormsne anr : , an an an.e accoruanro > camen oro ca,u conssn o :,, an . enca,arc , w meorreenarecu-ar- > consesnsc oa aoo seueencee aeas :.e. : accoars aneaos ca onme a,m wnoer aecn seuoee aeas encaoe seuence.e accorno cam, were suonscosenae. : as a comnaon o amnno aceo suseueon aseasscosenenaceao,aer sceuauence eoee aeas encaoe seuence : s s r weren conssn o :,,,,,,,,,e,ece,rom,erou e,, s acco,reno, c aan, o, ,,. anre o, cuare,r,, an . aea >ecene cnacmas,, m woererenarceua-r- > consesnsc oa aoo seeuencee.e: ac:coar. s aneaos ca om, wereneoee aeas encaoe seuence.e accorn ne amno ac susuonscosenae. : as a como cnaamon, o w aemrenno aceo suseueon aseasscoseencaoe seuence eoee aeas encaoe s nae,arcuar weren conssn o :,,.euence : s seeceromerouv.omeans a ac ccoomrnnaoon a on a onne- o-e arnece ann- cams, werene an-- anennn .e accoro an one oerecen cams-escre ae. :. , werene-oee comrses . a see accoro an one oerecen camso, werene-oee comrses .euenc aec seeceromerou conssn o :, an . covaenncoeroo a an-e ornmen ous oe sarece-n coames, weeren a an-ermnus o sa--s eeeneras aen oo amn eener,arcuar weren . reseue o ac scaoro- an oonee oee c aamsoo a,c ws.eren an-ermna resue an a-ermna oe--, re emee wn a comemenareermnn reon aercuearne wr oereno ao ameno ace cso,n asnsn- o,serom-ermnao-ermnarecon, a acs,s emee wn a oe- oee, an aeener oo amno mooreearecu, aanr a weerene anoer oe aem cnoons- acsns, o aeener o amno acs, an- .e accoro an one oe camsos emee wn a oe--. covaenneo a-e , weren an-ermnus o sa--s eee rmnus o sa-oee aeener,arcuar weren .e acncoerraos a anen one o oeo amno acs. nvoum recen cams, werennn oemrozuma or .ea acoco arn-o c aen oonees o no sncann suseuennn oe o sa ce. - e - co e camso, weren e seuencmrses a varaeoman comrsn aoee aeas encao - ee se-e comrses a v:arae anoman c :ouren omrsn aoee aeas encao .e acc cnce omor csaem,: we.reneoee aeas encaoe seuence : an s a : , a .e accor ano cam, w : . :. erene - comrses a varaeoman conssn o .oee se aucecnocreno an on:e o coe camso, wereneoee aeas enca an an mrses an: . : , anv.omean co ancscsornn oo a ano oene oe camso, werene - comrses a varae coma eavn aeas one amno ac susuonscosenae.omere a accoorno an: one. oe camso, werene - comrses a varae. -en co e ancscsorn -n o coom anrse osne a o: varae. ceamomsano c, weren e seuence : an omrsn aoee aeas encao - ee se- comrses a varaeoman comrsn aoee aeas encao.e accourennce :. : comor csaesm a, wereneoee aea:s, aencaoe seuence.e: acc aonr ano cam, werene - co:mrs.es a varaeoman conssn o. o ae va ac:cor.no cam or, werene- comrses a varaeoman conssn.era aocnco or : avn a muaonenenae. oe seuenceno an one: oe camso, wereneoee aeas enca : com arses an : , an.e accorno an one oe cnam anso, we : . oman conssn o rene - comrses a varae comareo ao:eeavn aeas one amno ac susuonscosenae.e accorno an one. o oe camso, werene - comrses a varae.mean co ancscosrnn oo an one o:e c. comrses a comnaon o - anams-oe,n weeren as ae r aonw-na aen.ennnoman. coe accorno an one oe camso, werene an- anennnoman am.r ases omeaavn ca-n varaeoman - o :, an a can varae aomeaavn ca-n var o oaeoman: :,- or o :, an a can varae c. aeav can vara or oman - oeoman:- or o :, an a can varaev . aomeaavn can varaeoman - o :, an a can varae.omean con asccsosrn-o a on one oe:rec.en cams, werene an- anennn a. o .ee --nneeoo a aH1 Lomomaan.n, an .omean co anccorno an one oerecen cams, werene an-- anennn as.ss o .ee----nneeo aH1oman, an .e accorn o aLoman. - one an- ano ceanmn,n werene consss o -sn oman, werene-sneo aH1oman, ane - one an:--e e anno ce a onL vaeno nnman noemaon we ane--- anoeene aeas encao - ancoeeoman comrsn ars an se nnoman, .e accorno cam, werene concon - oman. - one an-- ane sss o - ars an a nnnoman an . ane- a anccoernn seco non n ca amn- oma,n w a ssenrennen een o-neermo -nm eua rsn m o. nuse aHr1oman oers an secon an weren aermnus s an seconH2-Homan, oma o oneHomansuseoeLoe an-- anennn. anen. - a anccoernnnon camoma,n wsserene-ermnus oeH1oman oers an secon a neoe-ermnus ars an seconH2-Homan, enrm wnuesr oen a a oe ormnen auns- o-e anHoenen ann-- anennnomansuseo one.nsoae nucHec ac encone accornoman. .esoae nucec ac o cam o an one oe camso. .rno exresson cassee comrsn, wee nreucnece a ncuce accc aocrns ano cam. uner . vem r eo axe verre o csose conro o a. ror cna o cmaesrsn se a ne m aacm ecmo era xnan c ressoe o c. na cmasse, we aecrceonrne eox creasmson c.assees a asm.v. acc coer cnomrsn esoae nucec ac accorno cam , ore exresson cassee. e or, aocec coa erm xrnesso. o ann ca ossnee oe aceco cranmso coam,,e osoae nucec ac accorno cam or re vra vecor accorno cam,. e usen areccaornn cancer. e s amnseor an one o cams o or o or usenrean cancer, weren ano,ar eo aaen recevn concurrenreamen w an an-- anaons o sas navnomumaa,,cu moea remrr woarze cure umn aa s r,a wo asn earer- nma-, an e s anao n-mnas -, ans aneo azuoms na se s,e a cc neemro ommas,e s cees ere co cemnsas r,n or nvou reamnm e-a o n w-r ae om.n a nm earoonzsum ac aa cn. oronoo arn us oenenrean cancern aaen recevn concurren. comnaon mecamen oe cams o. - - ae as secen c aonm ornsen o:e sene acne-r-om anaeonss c aonnsosn, oar cc nua vam ors um waeo ,reen, m s aan ro azunm-a,-o asnaaromnas ano s sezuma, cemma, cerema, or sasanma, morearcua , snma, anaons ano s seecerom nvouma oremrozuma.r werene an--

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