Compositions and methods for activation and maturation of immune cells

Abstract

Mammals rely on adaptive immunity to protect against infections and tumors, with the thymus playing a crucial role by producing T cells that target infected or cancerous cells. The thymus, however, undergoes functional decline with age, significantly impairing the immune system in the elderly. To investigate reversing this decline, compositions and methods for activation and differentiation of T cell progenitors in extrathymic tissues are disclosed that stimulate production of differentiated T cells. For example, LNP-mediated delivery of mRNAs encoding DLL-1, IL-7, and FLT3L to the liver is shown to create a temporary site for T cell maturation that enhances T cell-mediated immunity in aged mice without causing autoimmunity. This approach facilitates ectopic T cell development from hematopoietic precursors and activates dendritic cells, providing evidence that engineering adaptive immunity in vivo can effectively mitigate immune aging.

Description

[0001]- - - euus,s a,c aanon. ca.mseene o..rovsona caono. ,, enre conens oe aove-eronvseona acacoansono. ,,er, .e reerencener enrees. areereuncororaeeren s-s acnosure was mae- w awareovernmeena suonaornsroumesrano.s overnmenas ceran rsnescosure. oea.e ,, ees c aonnens w oas creea eeec ornoncu suesuen,cesnseren- _.xm”zes enre. ncororae reerencens or acvane an suecer menaaernsco cseereoreennsorsenneraareceo comosons an meos oerenae ces. reessueso smuaeeroucon ssem, servne asmues sse ao vrae o sreeacnor esasn an mananne aavemmune ces.verme,emus une on,roeraon,eveomen, an erenaon onvouon, wc resusn roes ae-reae aro .e.,musnvouon ormc ces.s canncre ess ecen ceeveomen anecrease ouu o navena o es ase susce o oorunscnecons, auommun, an cancer.e mor ana morsa aa.vues,mmeruens a c naene asoor r ceosmuonsoonosr a vnacc mnee roessonosre aen smncureaasoen - - a snsem.erenaon o-ceroenorsn non-mcssueso reuvenaee aavemmune suc aocumeanons a ovraaene acsaroonr o ar anooecurmeseennnscoss aure.caons no an amssona erenaone ores ceenrosceonsuorresnroavreese comssuoessoo snsm aunae meeorosuocrone o acvearon an ces.n one emomen,eresenscosureroves enae moreonuceoes encon a comoson comrsna one or o ceroenor ces an one o ar meorveer ac vveance croonensureaonuecever cee oneere onr maon onuceoeso aaressue were ceroenorseren ore n one emomen, one or more acvanroenss ana ae. awa or a ce receor snanawa.n ano ons o aoc snan oc snanawa comrses , ,ae,er emomen,e aons oe anoer emomen, an aons ae, or a comnaonereo.n comex cass or c oassea snanawas a maorsocoma comrses -, -, -, o n.n anoer emomen,e cassan an comrse r aomooereo.n anoer emomen,e cass n ones emo-me,n,e- ao,ns o-e, or aomooereo. - or .n one emomen,e a oc snanawaoes no comrse comrse-.n one emomen ons oeoc snanawaoes no . ,e aons oeoc snanawaoes no comrse onuceone osn een ecmoonm saen, coe cnoems.ons aonnouerr eemr coommrense,s oene o or more cones or comrse-, , an,-,-,-, , or a co ne or more cones emomen, one or more cones mnaonereo.n anoer n one emome nucee exresson oeranscronacor . escr n,e one or moreonuceoes o an oe comosons roense aneroern c coomnresse o onnee o orr m moroere masm moecuse encone one or more acvan roens anor cones or a comnaonereo.n asn eoncoer enmoem oneen o,r meo orene ac orv maonre^ - - mmmunose cnomcr,s aen oonrem orrov meorraens maoon ecacoennscancrease m sa, reuce mcrovescen, on ae v emrao vmeceonr,, aene enver vece com.rses a nanoarce, an exosome, a nanosrucure, or an exraceuar conracneeerenec reornoe sesmeemn vecor, aonuceoe-ase vecor comrses a rerovra,envra, aenovra, aeno-a.ssonc aanoe,e orr emeroesm senm,e vra vecor. ex vra comnaonn one emomen,earessuesever, seen, smanesne,mus, or a n oenreeo. roenoreren emaoon,m saen, meeores ceonmrsscnosureevreorvne,so a a mearoeosrnucn ce roenorerenaon occurs, one or mo sue were ce roensanu reonuceoes encon one or more acvan n onec eemoeremnena,one o one ceroenor ces. evereo e or moreonuceoes areormuae soae are e surace oneo eneoa ceeas cneearessue anae acvanroens aresae on a comnaon one emomen,se.aressuesever, seen, smanesne, ormus, or roenorsnn oneer eemo.omen,e one or more acvanroensnuceerenaon o ce no n o ono neu e e eme- moos ommev ene n,,ee on oe ce n oers o m. ro mreo arec avcavnanroeronseo nonuce auommun. snanawa or a ce receor snanawnss an aons o aoc aons oeoc snanawa comrs a.n anoer emomen,e comnaonereo.n anoer emomen es , ,ae,ae, or a cass or cass an.n anoer,e aons oe snanawas an , -, -, or aomooere emomen,e cassan comrses - comrses -, -, -,o o.n anoer emomen,e cass an n one emomen,e one or mro areomoonouceereo. comrse one or moreasm s encone one oro moerse o ac anva mneoroseness,c ornee or meroerne^ - - m emosm eennc,oen onee or o mneor oer m mores ac covmarnse ornoee onrs m, or a comnaonereo.n anoer sa, reucemmunoenc, anorm ore mocaonsancrease m n one emomen,e one orro mveorreansoanounc ecenc. nanoacrecoe, an exosome, a mcrove eoes areevere va a onu sce, a vra vecor, an enneere reroeemen vecor, a ne o-neas eem noanomsernuc,uree m, oer aon exurraceer cuoamr cronsersaceevenrnec oonn ssem. onuceoes encon one or more cones e or more cones or cones comrse-, , an,.n anoer emomen,e one or more ereo.n anoer emomen,e one -,-,-, or , or a comnaon acor .n ano or more conesnuce exresson oeranscron or moreonuceoese ernc eomnomeen on,e oer o mnoere or ac movrae cnoroneesns a.ren c aon-evere we one cones areevere searae,emora or saa oer emomen,e encone acv ,rome one or moreonuceoes n onanroens. cesne emomen,e one or more conesnuceerenaon ooue-os acvanro oenoe s ns en ,me ve n oro-o coms menv n,e aoenrese cnes.scosureroves a meoorenn canae erenaon, sa meo s o acvanroens,anuce ceroeraon an or more canae acvan cormoernssnaaneucever cne one oerre mnoareono onuc ceeoreose enncoor cne one aouaon o ceserverom assue oneres, seecn a same so exressne canae acvanroensromeouao o sne cone cesneres,crean aouaon o ceroe n o ceserveromessue o exressne canae acvanro nors w e same o sne cone ces romeouaon o ceroeens,uanneercenae o ceserenae canae acvanroen nors, ane seecneonuceoes encone eerce sa resuen ce erenaonor evauaonn vvo, weren eernenae oerenae cess a or aove oeoa ceouaon conssn o or a comnana oe onne em ce ereos a o.mnen, ceesrsoueen oonrse.ressever, seen, smanesne, ormus,^ - - n oesnee a enm ooemr aesn,ecse, s oameces, oe sanure cone cess seece usnow comer. wecome aarenooseavn ornar ses,n ane a arva unaone cso onseer eaxaomn oe emeooomens eaeescron o exame emomens. wn oa n unersann oeeaures an avanaes oeresenscosure wen wncee rerenrcenceeso oeeosocwosnuree maaee uescrze,ona sesorusrave emomens, .ecsesuncon o co ane accomannrawns o wc: . ecs a sme moer oca cemecve eea cesn an mce. -erve commonmoro omen sarnromone marrownoemus, weree renors an muoenroenors omn corcamc eea cescecev aen neereanvae soene sconnaso sroowmea anoens-vrees seeconncun meuarmc eea cesms.aure+or+enn ces, cesen crcuae ssemca,ncunne sec sne-osve m noes .,oue-neave, onarmo orans seen ann n + = anma.s o s vaorwosus aeeus.annecaar roenr oo e curcue-aonsve.s ca-+c-+on-ra+n n = a.nma sso ows varuaonus acaes.on onea cs rrs rceuon ra s esnown. s s+ +on-ca-+c- mononucear ces.s ac-ross s aoew.sace reoasveera vcaounon e o s cowrcnu.an s wnveoo annoaese aver or one mousen = .e arrowea s.a-e sar s oow macroscocmcnvouonn mce. cese,. a se caneso seece ce-eneracons: c w earson’sncaen. m-vaue wenoes s censcarnce, o.earson.’sn ceoarrre reressonoe an arrowea annoaese averae sar o ma aon w ae.e osemonsraee av croscocmcnvouonn mce.on cacuae usnwo-aeera uennaererac-oens zs-.scoresre- anos-mcnvouon. vaues were^ - - sren w as.e.-ac s roowseecreasn receor-anneraconsnormazeneracon common receors onws a un.ue o cre-anes-c oen-e ce receor-anar ans annoae e averaeneracon z-scoresor seecneraconsre- ansos-..ar carsemonsrae were cacuae usnann mcnvouon. vaues on -neess.ors.-, n = saa arras overme eecnes.or s-asnn r aencaesors-:anuneranceoraon oeone anmna were useo eac receoran ce-cear acronsss am eaec wemree emon.useuen,e mean vaues o correaon an avaue.er correcne-vauesrouoeoone crarocnua coeearman’sneracons were caeorzenooseecreasn anncreasn w aeor vrsrueaczon, unue .ecseormuaon an caracerscs o n aon. conann anoarces s ., s, aonws ma ms on. ms. earzeasms useorn vroranscron o .. s soowws aaee eeacroonoressc oreenn vareo rersaunscsr oen- an cae ms. ms. vroranscre an cae nanoarces.s. sorwees m eenacsaurseumaenosn ea ecc oenwcoesn oeene-nconaacnens sow- mean s.e.m. vaue was cacuae n.aa are . sows am uesenr a awno-aoe unare-es. reneanm.c scaern.nvua aces sownsnerrse, anvercaese cacuae as a mnea ssuorewnn s..- sowsaramoanr oeaoc mesran esxecreessonnmmorazever ces. oecamne™ an suseuen sane w an- w. m n. or surace exresson o . monocona ano -^ - - oecamne™. so awns surmsearuenea soacnees wrans aence- w mo.no m n. or surace e cona ano - or .xres ssoown oercena.e o rmareaocesosveor exresson o .. .: snorwavseneorcuesnanee oce - cesosveor exresson o or . anmas. - smrovemmune resonsesn ae .s. s-ow ss ao swcsemuac ore m ever. surace roen exressononremscmenocreamzaee msouse.ea anuancaon . o m n. oecamne™ an sus ocesransece w. or mocransece.- euen sane w an- ano ar, m. aenn sann was useoeneae ce memranes.cae r s.ecree sowsmme exraceuar concenraons oooca acve-e an - m n. ooraezeeaocesransece w. m or. eermne - an camn,e r™esecve or..aa ar eem meano s.eec.mam.ne v™aue as cacuae usnwo-ae unare-ess. s were s.- s n =neenenransecon exermens. . rmareaocoewss w mererea-eus wee.aoces sec mreeronces.se oec an-. or. em oecamne™ .. rmareaoce amne™ . - m n. oecamne™ or. em ose werereae w waserorme usn an- an an-- m camne™ . . sows serum an-eveonocona anoes. se oarnusc.e.ms.erumeves sn mcereae w eer m are m measure an- cone , resecve.aa .. v sauoewss were cauccuaerease usmna anwo o-ae unare-es. moc- s oruc- snravenousoxnou-rs- mecoeremaaanve. re=cev mece e.er^ - - . s.- –n vro ce mauraon - s noneroro-nuceee.rena soonw os scemac oroceure useo sow -exressneaoces . so cesromemaooec sem ces–n vr–o. rece+or ne+aouve ws eosve–er,cena ,–e o sn–m eouoc ose ne ves eaave a,re ce receor-ouosev neeave, ce, oown co-ncuaon oemao , or sneosve , - or -oec, sem ces w eaoces exressn or - or w sroma ces exressn - s.. s-. ow –scereernocneuorernor v scrroeennereonr caoon coca comnaons.nuce ce eren mnaons o acvanroensa coems wneareo unssee.se, w saoewo resn. ne reaveercenaes o erenae cesor eac oe c e comnaonseneesercenae oerenae s..orn- vv acc –o nnes a vn ovno. scesnnmmunocomeen mce. m n comnaon eue useo evauaee ecac o s.- w sows-eream men o asnm amc mce. nuces maure ceeveo c mce w reerena roucon occu.rsn sowesv aer,raoecoowre ome an cr. ocnae-meroauece maur caeosn.ne-moeoa ane se ceen. roa o nu amemr oc mc ceerseaaerve wse eromevere,ereraoome, an seen m n comnaon w cmones. nean reoaarvecerso, coroonne os on ce,sa m a , or neave ,oueosve , sneosve , o reoue s sown. r sneosve ss..-- s sooww a arrccaammuuss--rroouuccee c ceess c caannes aecavraee ce exs v.vo.^ - - moce rea.con sows o aa cerasme orveero exme srmeeennsa o seue mnceor one-se mxe anmas as eecor ces an senoce -reae ooxn-- -nuce ces s asare ces. -mce are ce-ecen an roeraon ass were aonaaee w o aow unamuousencaon an .essm seonw os esoecroarm cses aer e or wouare cesnrca.nace asunoaranmce r aenresreonse ornaeono ooca rec caees . sowse asoue couns oare ces - aer mxemoc. reacon .acose vaueor one mouse. n = or e : raosnc a conons.ecor-o-are s..ae. s-ows sow anmmune an moeor cancermmunoera. resonseueomcnv aon ouveornvenw m ocee a ensa sussemeune o ae-nuceecnen an-umor comosonsescreeren n evauaon oreamen w e an a searae con .nerou o ae mce wasreae w n=, wasnocuae wro arou- wasre maeean woma e cmene onn=a. anoowreanere wamen, eacrou ano everreeas.umorrown resonse an an-- overa survva were ev ommune ceconocae annocuaon ws.-- sa mou ewae ano a. m caom ceasrs aonn s ousuemuor szen ae mceoownumor ocae enreamen wmmune ceconnocuaon w.. - sowse overaroa o survvaor ae mceoownumor . sows m aeanaomraam ce os ane eoxoewrmnenraea smeeunen wceo arn s-ucu-ane aono.manaon w . -- cesno mce ae weesounus oumor weesaeoowe woreamens w an--na sucuaneo r an measuremen oumor sze an survva ana us, e exermen.a en soowns. aauaan arec maeaonn o s.uemsosr. szes a, weners anma reace unare-es. .m. vaue was cacuae usn awo-ae^ - - as ounen.. va sueo wwass a cacauaane-eer survva anass ooun an ae anmasreae oun an  usn ao-ranane-oxes.oun n = , .= , s aowesumornm =m u,n ae an = .ndconsecuve m. sowsumor szeoaenracms exnder emxeenram wenor.oawcn eex reerrmeseenns.e e exermena.easur en se oonwusm ao nr du s eaz xne va ermcaues enon o . o one auam m aoo reru m ssez. eeasn a s.e.m,. we vnauee warss c aancmuaae rea ucse awo-ae unare-es. nn. .ndexe sows aaan-eer survva anass o ae anmasreae as oune oro cononrmen. vaue was cacuae usn ao-ranane-oxes. n =  s..s. s-ows s aonw osv aenrvmmune an moeor vaccne resonse. re ew o esasmen o ae-nuceecnen vaccnaon cosmonosseonuseoescrmecenrevon.uonnn mce an suseuen evauaon oreamen w e an a searaerou o ae mce weasroruea oe a we m emce wasrean=e w.oownreamen,n e=a, rou wasmmunze w ovaumn w comeereun’s c suseuenrove aoosermmunza auvan ona an ona.oownmmunozna won, o mvaceum wenre wreanecom wee ovraeuunm’sn a-eurvan an ce aa:ve re asnonse w : erve ees, amer .eo a sorweaser aner acneanasass e e o ovau oea ure. eeroasveoorawn aa reveaea s. sowseercena ces. ces e o : eramer-secc .oae sroowms eeroeer-asecooc, s secreeeno,n over,r aannzmemus.zm,-, an- nouns. mce-o sunow, a a ceom marcesorn . ces e oae w m n: comnearaomne wr-sec-c^ - - m nanoar ance m e , an ae mcereae w em ercenae o.e sows.e vaccn:aon reesramonesre-s asec ancmm ceunse aecnuncon, weree am. sowser reases w ae. : er eamen w can aumen .er-s secowcsmemoune resonse wees. - r ae canennraceuar cone exresson o-e an vece. n =  anrmas reocrao o s conenoconess. waa are mean s.e.m. vaues: we reaveo usnwo-ae re cacuae . una sroews-eses w. e vaue es o exane seens a os vaccnaon.acos cacuae uosrn one on meo-use. n =  anmasor a conons.aa are mean s.e.m. vaues were oces.cae wa oowewo-aeunne’s mue-comarsonos .aror s reresenave seenmaes, cm. eramer-nn ceoswnse reavereuences o -- : one mou seense anereraoor.acose vaueor wa se. n =o oowre a conwo-oanse.auan are mean s.e.m. vaues were cacuae usn one- . sowse re ne’s mue-comar-sonos+oces. acose vau avereuences o nave cesn seens. cacuae usn onee-woar one mouse.o n =o or a conons.aa are mean s.e.m. vaues were oces. wewo-aeunne’s mue-comarsonos econ orero.nom saowsuaeraoncunernao vaacocnn oa ron exermen o mce wncreasn ae. : eramer-nn cesn seenesavereuences o -- ,2=..s sanar curve w conenceans sown. = nu was useoroece “vaccnaon resonse ae” o vacmcenracaon.ac-weeo-ose a vnamuaesor oane mavoeuseenre-reae w oruc m roro ae vaccnaonuc m n = , aee.a vcaccncanea aonnmas m =  n =n  = er. ae varouueo,^ - - c aomwo-araeee u ensmaae vaccnaon resonse aes oeworeamenrous was cacuae usn comnaonresre am--es:.ne-acoreveroes nou recauaee eecs o w vaum.en nn.. o maram- oe- erxeaeermena seuenoceoowre sucua mneeaosuusremeene o vac vcancacnoennuce cesow comer.am vaccnae mce were us - ..es o exane seens a os ve as neave conros. or one mouse. n =  anmasor a conons.aa are meana sc.ce.nma.on v.auaecsose vaue usn onewa oowe wo-aeunne’s m were cacuae ,oun, ae ue-comarsonosoces. nn ces.. ne.reearaveoroeu.enacces o -- : eramer- aa ose vaueor one mouse. n = or a conons. unn aere’s mean mu s.e.mec.om vaaruesson weores caoccueae usn one-wa oowe wo-ae nn ces.ne. seeaenv.earecueoncses os.,oun e vaueor on-e-, ae. mouse. : eramer- are mean s m.e.m. vaues n = or a conons.aa unne’s were cacuae usn one-wa oowe wo-ae .u.e-ceomavaersonosoces.,oun, ae. se vaueo reuences o nave - cesn seens.aco usn onewar one mouseo. no =w eor aw coonons.aa are mean s.e.m. vaues were cacuae ,oun, a -aeunne’s mue-comarsonosoces. ose vaue.e. or. onee maovuese.re n u=e ncoers a o e conecorons. - cesn seens.ac cacuae usn o aa are mean s.e.m. vaues were oces.,ounewa oowe wo-aeunne’s mue-comarsonos ose vaue.n or., a oneee ma. ovueser.e n u=e ncoers a o m coenmorons.aa are mean c se.e.ms.n s vaeeuness. waecre^ - - caoccueas.e u,sonu one wa oowewo-aeunne’s mue-comarsonos serumeves.sn.,- ae s.ow m ever resusn a s ncrease o ,u no- m. . sows serumeves o-n amc mceoownreamen w m.. sows serumeves o n amc mceoownreamen w . exermens..: sow ms aaoersa nmo onucee evxereromxecna seuenceor sae anass m n =  o.r so mwse wn e= s o ae anmas weesreaeoras wuc weesreae.or saowss wveraun.cno =n ar,ameer ms measurne =n serum o ae anmas n =  sown.aa are m   or recomnan- anmas we.es sowesan mu s.e.mex.e cone measuremensnereraoo o ae - n = .reaveeraoer conceansra won oa en = , m n =  or recomnan o . sows a reresenaveow cacom aneareasn so swrna.eouanreuenceseramer sann-- : secc cesnereraoo o mce om.. user svoews aaram ooue eex-eorsmvenea seue cnecesonr =. v. ao.ve m cece,raonserna orano ae recensn =  . mce a oe o successu no e weesoowe vercaon . sowos a renaveeecreonue annces oenon. oner.e cresnm an seens. me,, seenoom,.acos aooo,,mus n = , ae . a e vaueor one mouse.e .ae unare-ess. n = .aa are mean s.e.m. vaues were cacuae usnwo-^ - - an sne-os.ve sows re.a cveesrenuencmes an o soueenes-n oea rve ,oueosve one-w.a n = .aa are mean s.e.m. vaues were caeccuaeens us an re aeeare me.asurees soowe a mue-comarsonosoces. .. s-ow:se exroemoes ecoc ceeveomen. oxn- / -mc rmena woroworreamen o amc.-oxn-- oreamen.c.e w aea sr,ows or m.uoru eecsrceesnecnes amvae oes oreen+ceeesnnen ex exaneremevnersoownas cees,ne+. arenc+sow ma o ces a exsamow c neeo v am ene rs rr oeau owvaen nraccaoanon s o o as+oue c+ounss o ces o+ces+conons.aa are oreamen. n =  anmasoro s. m-ean s s.oew.m s.n vea-ucees were cacuae se uusenncnwo o-ae un care-ess. verarencma o -reaeoxn-- m essoaerom accornoean sow ce aa ens cenruaonoowe arencma. ce srooewn aorn ceorn smn wan. anno. oaonsroxmaon anroecon over- ensos o rer oreeranscrona cusers-e,reae anmasesenave marerenes , , r. = m- ceroeno. n = rne so swns ae ceeamsaos oe. averae reave exressons oemaooec an s overanasaese m aanrer,s,a csee-esveecomcenase-seccranscronacorss, -enen s, an enesrc anracn cusers .. s. . soowwss a sa rom. annoae saus o eac ce. an canncanecroeoraorn c aanrs a ssoue e nxumeremre on r reearracnaonmce or anroucve canso anero emens o unroucve soom. oron oenec evenseano unroucve^ - - recomnaon s.aus sows aeama oerena exresseenesn ces s ces o . ces s. nowesr aeorwa cooomer anass o reaveracons o one mous oown as oreamen.acose vaueor awo-aee. n u =n a arnemasoro conons.aa are mean s.e.m. vaue was cacuae usn ereraoo.oo s- woews ns.e raeas overeraacmeonn. oaco anse vaueor ces o cesn n = .aa are mean s.e.m. vaues were cacuae usnwo-wa one mouse.oucowne = ,wo-aea as oreames.’sos-oc seosw.e seuencn oereraoo samesoown .n. . s soowwss r ae vreono o overamson cona sown. er re senaveree masaenoee uoo cones an resecvaev.eere.ueanrc cesar wsencnee num reere orore o auc an -reae anma, ose vaueor one mouse.ucn = , n =  un.uaea are m reeaarnran se.em.ensr.ac cacuae usnwo-ae unare- m. vaues were s.-: essore numer o unue rearranemens anmas. cocaeveoe ces accumuaene seens o amc oown as.s o-ream- / s -enow. raecreseonasvee vmaaueesor on aen m wouese.soxn owtenx = an,eo sxne-e / -ns cauccu mae usnn =  on,e-woaxn moon =  anmas.aa are mean s.e.m. vaues were oces.caearor reresenave seweenmaweso,-a cme.+unne +’s mue-comarsonos seensoown. saosw osreea remaenv.earaccoon ose vaueor one mou cses o+cesn m n = .aa are mean s.e.m. e.uc m n = ,es. vaue was cacuae usn awo-ae unare-^ - - seensoow.n soawss oer reeaamveen.racacon oos+e an+ces o+cesn conons.aa are mean s.e.m. vaues were cacu vaueor one mouse. n = orowo-aea’sosoces ae usnwo-wa oowe .. s soowwss a re. eresenmaave wor-roowecoronn o s mua soenoceron. ce suesn weusrom w- r cees an ceenrc . sows:o:eaveemmaure cuec m ace. uc mce normazeoe unanceere o vew n eave nave+ +ce aun conon. n = uc. e: normazeoe con anceere o vew n uc mce n c = aunanceere oo u vn. ce n .w = vaues anre cacuaeuc m ucneuc a no. rremoao wzm oe: -oeaeve na covne con. . sowseerenaene exresson a se-es.ncae acvaon nass os across conons anass o mao. o a r ce sows s au nees.oroo enrcmenuancaon ce-ce aacenc arencma..-e:s.aracerzaon o ecoca enerae cesnever o . sows a reresenaveow comeran sraeouanreuences oxnnra--a arennmcama ceroenorsnevers o oruc m-reae roenorsn.s. e sveorsws osor oarmsucn mcan-reaee aunoxannc-e- o anmas.acso ce reresens one ram .oo scaow res acane.ormano roxmaon anroecon over- marenc-rmeaae a cnemaroseenor ces w annoaons oewoooca recaesrom = m-reae anm,asen ns =o ssn o ree creessenoasve m.arerenesaa,rcr.^ - - acorssa.a, s,ows a aesa wmea a ssroawnsnc averae reave exressons oranscron recomnaon saus an exresrs oe comex , ,e s . sows a reresenaveows conn ceroenors. o ex vvo maurever-erve ceroenorsroommera mn sr-areeaeoouxann-- arneuences cuure w ornocou senoces as anen- mas co- racons were ce-eee anver- resenn ces s.o aow unamuousen erve ces were aonaaee w arencma. cer sooewnso aca rs wuo ean rn. e coc-acuonu oow comer reaou ounen.ver roorons o ara re w senc sorasroro anass. an or snnseerroes avneve ce cse,sou soew-nne. na = veoo,ca recaeosuoe-osve aa are mean s.e.m. vaues were r a conons. unne’s. cacuae usn one-wa oowe wo-ae s..- sow:se eexmoernsmreaneasa wvoorraoewoxoces anormemunevoeoocmaen sae. aees ..-cracr .esavs . mceransenc oore auoreacve reconz e conr n - : ncue asosveevesorou m.xernmwenoan eneenonen mnesaesu oremen was reacen anmas wooucose . sows aonuna s orn anmaseveonucosura. seccsneere ooucoseeveso anreuenc o -- anmas.reae s aosw osu ara nao eao nn-eo .eorm annsa o e oss o c aunmm wua asas evreeae nea ae as se osu nncne .encne v ana.ss o cacuae usno-ranane-oxess.. aues were m n = n = , uc m n = ,aree ce. . mmu sows an exermena worowo monororeeveomen o - reconzn257n-264.ncue- asocsravcer conrorou-or mce-rarnvsenencor-aeree^ - - reson32s9e-3s3,7nc.u.e- a ssc oor wsacvre conronrouo-r m-crevernansen-caroeree resonse rse.conzn eramer-nn cese reavereuences o -- : conons.aa are mesann se.er.m.era vaoo.acose vaueor one mousen = or awo-aeunne’s mue-comaruseosn weorse caoccuease. u vsanue o cne-wa oowencae. omarnc-m rous eramer-nn. c seoswsneer reaeraveroeouences o -- : conons.aa are mean s.e.m. vaues w.ereac caose vaueor one mousen = or awo-aeunne’s mue-comarsonosoccuease. u vsanue o cnoem-waarnc-moowencae. rous ucn =  or.n s =o ws m an an-or as an c wae snerea oc-m m vcereae w oos or sam vaccnaon.accn accnaon an use asosve conros. s ae w-e, n =  mceneraconsn.e s:eema450 nm -570 nmenowne.s ecocaenerae ces an new ce-ce ua conro. ces.n weos rm o e cuuao-nraea weor mocew.or ce n o senoces ma.er reons wereurer cuseresere-mneaon rse cuosnsern usn anse ce msneene weu ..ene exressonoosoreve arerenes. ..ene exressono cusern o maor cees. ..ene exressonooossoorreevvee c cuusseerrnn o o m maaoorr c ceeeess.. ecocaene..ea ma sowne reaveene exressonnormaze eneor .rae.e ce sues. sues. oroo enrcmenuancaon anass sown a ce .:cocaenerae ces areuncona.^ - -- anmasor.a.soaorwame o soer ex oe srmeennca s ceeusen anceoer ou mneureamen ooxn- mce were use asosve conr ncona assessmens.ncae reaen.s.a.ceaovseree vaueuneceoso r o os. ne mo-us-e.o ns =ve ces aer acvaon w e s.e.m. vaues were c  or a conons.aa are mean mue-coma acuae usn one-wa oowe wo-aeunne’s .rson.osereoscenesa.v neu,oowxn-- w, . cone-roucn ce comeran sraeouanreuences o ..esa aveer erxe vvo smuaon wencae reaens. ncae reaens.acose vaueunecoers o one mo-u-seo.s n =v eor a ce cson aeron asc.vaon w e s.e.m. vaues were cacuae usn one aa are mean mue-comarsonosoces -wa oowe wo-aeunne’s ose vaue.or o.ne msoouusee. n c.  =e nu   c,oouonxns-- w a,er acvaon. wencae reaens.acanee.auann aree’ msean mu s.e.me.-co vmauaerss wr oner aeo c c saocn oucaeeons s. u. nsunase ,o oxnn nee--w-a vauenocaoweeoweo- ..aram oe exermena seuenceor on we-,se mx. reacon o ceserverom seens o m-reae ooemoce eecor ces an senoces asare ces xn-- anmas as ces wenre o a eonaaee .-mce are ce-ecen an -nuce assessme w o aow unamuousencaon anroeraon eecor ces an.eco un.r ceesr.esenaveow comeran sraeoen -aee .a.eseoarre ces aer . aer e or wouarames censcran.eac aunsoancraem an rerersoenesra onoen oooca rec caees .. meanuorescencenensn eecor ces aer .ac. os aeer vaue.ora ocne moousse.e n = va ueoro ar o cnoen moounss..soue couns oare ces - : raosncae. e. n = or a conons.ecor-o-are^ - - acose. vaue soorw osne mous me.e n =a nourorescencenensn eecor ces aer . acon mec.an ssmo.ws as,raca na overve aw c ooneo exns.ermena aroac aneroose ce ,oue noarces , ce receor,oue-neave e-ousresveere cne areo, sne-osve ce. scae. rusraveuroses on an are no necessarrawno . meann as cnoemsmsonene un oerseorwose,e ocnen oca o arnna srce sncnermes a urseo werecnavseseco sasume erans.enons o commonerms anecnues re oecuaronn:aorndn moecuaroo maeounn oecuaronn:aoaraoorranaunaua,,the eonon amrereono a,nrsacm,r aonoanas roocosnoecuaroo ..usue e a. es. urren nzmoo caemcress,nc.: :rac e sereseosn ames, an..aor es.:nones,aoracoararnouaac ar.o.wa acnearsnoen,, es..:. noes..reasonrea,or e.aneunaa,mndeewonn,enes.,.ureesnee e.onmaeuure enrew e a.es.,enccoea ooecnes anare, acwecence., oer.eersuaer.,ooo,use anoecnoo: aomreensveeseere ecuaroo neon e a.,conarnc oe,ucrse users,nc., e.,.e onsewor,.. ,ar ooo anoecuaroon ecansms anr c,vancerancemsreacons, anan vaneursenu,curraensen ec.,oounseeeoso annsreowoor,nd.. aren.oer enen:eos anroocos,or:onu cos, eon an s useeren,e snu nuo,user:rnerewor,. reerens unesse conexcaes oareorwrmsse “.a,” “an,” an “e”ncueo snuar anura^ - - crcumsance,e ore srums “ouenona m”a or or “o maon nao o”cc murea annsaaee suesscerueonnnescre even, weree even or crcumsance occurs annsan cuesnsances e recaon o numerca ranesc eens woenresncoeus neso a. susume wne resecve ranes ane rece e numers anracons vaue suc ase aearrmams “eaero,u an” a omr “oaun,ro axemmaeora,” aus usneoenresn. wen reerrno a measurae varaons o anrome sece raon, anee, are meano encomass oress, an-. vaue, suc as varaons o- oress,- oress,- arora oress o anrome sece vaue,nsoar suc varaons are moer “eaoou”er oro “rmanroxemaseco”s reeersscso asusore s.ecsc uane,rs anooreaerae, vausceoose wce s useeren, a “ooca same” ma conan woe ces anve ces an. ers.eooca same ma conanoreerverom a “o u.”eorers ce scosure encomasses emomens wereneo us seecerom a en aueousumour, vreousumour,e,oo serum,reas mnocu, earwax, ce, cme, enom,erm, m, cererosnau, cerumen asrcuce,m, mucu exuaes,eces,emae eacuae,asrc ac, u,eurau,us,sncun nasaranae anem,ercarau,eroneaear reum, sava, seumsn o, semen, suum, snovau, swea,ncsu,e ur cnee, c vuaurneas, seocreonu, vso,m ce a cnu murexsurroems oo one oru mso.reoereo.ooca sames rom a mamma oransm,or exame,uncure or oer us mae oane eerms “suec,” “nvua,” an “ae coecn or samnroceures. reero a vererae,reera a ma n” are usenercaneaereno nomeo, murne mma, morereera auman.ammasncue,u are aneroen o aso, somcaans e,num oansa,naermn an vmvoa osr, s cuorur aenmna vs,ro an are aesso. essues, ces, n an emomen,eerms or are usenercanenacomearsese. reero m n comnaon w - ms or no conann , an- ms nanoarces s anmmunen c anec emoon.mmenm,u annem cmecuneo c. nesc aroen wennoowrn manee a anr m anoecnuceuea, wnous^ - - ,m anaon,-.,n som-e e,mo-m,en,-,-, ,,, , ,- roen.n ceran e s,enors an ano aansemmune cecon , e.., an momens,emmune ceconnors annor o- or- cecon anoa seccans- or-.n some emomens,emmune one emomnen,oresm nmvouma,emrozuma,muma,urvauma, or aezozuma.n a une ceconnors nvouma. emomens arroeu nso emneonmee anss an ar eexaeuscsrveeesecrrenaone or.r as s aomue noeae secc scusseeren.ne asecescren c aonoeroaer asecs necessarmeoa emo onuncon w aarcuar emomens no eerencerouous seccamoenno a “none c eamnoemreanc,”ce “an w emo anm oen,e”r a enm “oan emxens. emomen” meansa aarcuareaure, srucure, or ame w e emomensncuen aea caracerscescren connecon aearances oerases “n one emso onmeen em,”o “nme ann e omoemreesnen,” orsc “oasnur eex.amuse, e sammeo emmeon”n varousacesrouous seccaon are no necessar a reerrnoe an suae mumren anenremu r,o arse m,a. wouearec auaarreenauore as,e srrsuocnu sres,e orn carea acrerscs mae comnen or more emomens.urermore, romsscosure,n one no oereau we some emomensescreerenncue someu emomens arere mseanncuoee wn onere e smcooe omenes, csocmosunrea.onosr e oxameaeures o eren cams, an oe came emomens cane usen an co ,ne aene u are noneens oer suoneuse mnaceee u ssceoen oe seecrecaonomrena sooen c.onvenence oe reaer scosureo an susecon, senscosure orom an asec oe erencororauecao rense, s renuu cese oe, or e saa aer mnara e eocu.mens, anaen acaons ceeren are ocumen, oraen acaon xen asou eacucaon,useaen reerence. was secca annvuancae asenncororae^ - - . erenaone oresen cescroosuerneorrsovne nso cno-momsconsssu aens moe somusaore acvaon an erenae ces.e comosons an meosescree eeroucon ommune resonse were cerouc ren can resore an aave enera,e comosons comrse oneo onr msoremonsnueceoueeos encmocn ar oone or o mronrveo acuvon.n roensanuce orromoe ce erenaon o ceroenor ces an vece conureoever saonuceoeso aaressu , an aever erenae.e comosonsescreeren m e were ceroenors suec exerencnmc aro o aeevereo a suecn neee.., a or morearessues.nceaen urnvoeu ceons c,o wmerresnne ceomaroesossnuse asr,eer oencee oo one onuceoes areranscre anorransae,ene one r more onuceoe ma encoe acvanroe or more acvanroens.e rcuan cero ns exresse one surace oearessue ces. ssue, m enorsa maassrou or oerwse mae conac weare receorsa onneera scur wace oe aceva cenrrooeennso nrosw. eoxrr eexsasmee, aearessue ces vaoc exressnoc manerac w aeac ce exr crcuan ceroenor va aoc- neracon.nn oe acevsasnnransencea-ean ssue cesoeoc receor one– –o roen one surace oarenuces a seres oranscrona eve ue neave ceroenorsno+ +oueosve ns ceas.eaoeerenaon oe ceroenors evereoe suecn neeer useuen exosure oe ceso conesno+or+sneos eonucese cesourererenae an maure roenorn aenroenearo asne ccom,ve resnreseen ces. versnco,suore araorveess msueosornucn ce erenaon occurs, one or moreonuc e were ceroenornuce orromoe eoes encon one or more acvanroensa n anoere arseneca,one orese cnersocoenor ces. acvanroens, or comn sureroves meosorenn canae erenaon. aons o acvanroens,anuce ceroeraon an^ - -mmune resoens ceom woerseon cse anro meucoonssescrmneseeren aresse neeo resore aave non-mcssues anresen .ever oe comosonsoare aernav aon oe acvanroens an coneserenrove an encreeas eenvrroonmucenono or nna vvveo an meraenureaon ce o ceroenors an mauraon o ces. rovearcuar useuormrovn vaccnes e cancamcro anve a cancvaem oumcuonmee rsesnon csaen anmmunoe cer . ra. ceroeneorrsesnen non-scomsurcesroves comosonsore acvaon an erenaon o one emomen,eresenscosusuerseor sovmuesae a coemroosuconon co omrsenrenaae one ces.n onuceoes encon one or more acvanroen or more ceroenor ces, an aever vec sanuce ce erenaon o onuceoeso aaress e conureoevere one or more como ue were ceroenorserenae.n one emomen,e sa csoonne maurer comrse one or more cones or one or moreonuceoes encon ces”, “ css. e userecuerrseonr,s”e, “errmec “urs coer croeesn”o,r “”umsecnroercenanoreas”, “ wm “roenor ces”, “ear mcroenor ces”, “mc seenr croenor acaeerm orermsnown one oenor ces”, or w an oernucueoerenae a sene ar reerso an ce or ceea mae ce s neveono a ce.eerm ma encomass an unerenae oeuceo anos svaee o c cees.evxeamomesen o u coe,uro noennocrsunncueeruen arae noonnmo emaooec sem ces,emaooec semrecursor ce eo, uroen sem ces, muoen sem s,uroen sem ces,nuce s useeren ces, muoenroenors, oooen sem ces. an s ,eerm “erenae ce” reerso an ce or cee sueco -a sne oeo ceeveomen, weren sa ce or cees a ce, a cvansroveensa cen, ourc ae-ce- eren cea.on^ - - encon onee or c momoreos acovnasnescrroeenseraenn muace co cmersee one or moreonuceoes ces.s useeren,eerm “acvanr renaon o ceroenor roenoroerenaen oen” reerso anroenanuces a ce ce or meaesosve aon aor neave se ce, a - ce, or a- more acvanroen econ o ces.n one emomen,e one or oor mo ss an aons o aoc snanawa.n one emomen,e one cre acvanroenss an aons o a ce receor snanawa.e omnousceoonsescreeren maurer comrse one or more cones or one or more ses c eoncon sa cones. comrsn one onre mmoreaeonnuceeoreessen encoscnosu ornee, ore m coorme aocsonsescreeren, evereo a non-mcaressue weren c vanroens, cane a non-mn exame,e comoso e erenaon canaeace..n mraeoever or seen vae crcunsaoersc srseem.erencne caanene uevereeanc orarv senoenusc c an e one or moreonuceoes areranscre anorran es, acvanroense.., an aons oeo sae,ene one or more e exresse one surace oe ce c snanawa or snanawao oerwse mae con s.rcuan ceroenorsa maassrou or exresse eeaacc o wr senec cveers o vra soeecn, r mecaeonrser oanc we suracee a ocvanroens now orsne case e ceroenors ocnan oaweraenaoe ces. erenaonn o one c eemoromeneno,ns rs mes a o cnoem orrse m aonre ao acnsva on aorcoe snsanuce ces aransmemrane receora reuaes varo nanawa.oc erenaon o mos ces,ncu usrocessesneeveomen an receors anve ce n ces.eocamncuesour ce surace oc,oc, ano sucrac.eeococanasnns maamnmoasw.oaemouers renceowonr ass conesas- oeoacns, oa,e wc an conasse o. ,unc,o anns as an an, aanonesrra oe-eseeaaens, wanse, we rcem caonnsns^ - - coaunroncaan ssn , ,ae, anaeuncon as aonss.oan e a.,e ea cnawa: unone acvaon mecansm,e, ,:-. avn an exracaenounacraomoacn a rence anornsr aaceranusmaremoraneroen exresse as aeeromer, eermarowacor -e re man.e exraceuaroman conans sueonsa eas.e., reeas o sx csene resuesaormree , ,aen, eaeern ourceaseans.enn o an aonsane.., oman oocnoe coa roeoc ceavaea reeasesenraceuar neracs anorms a comesxm w.eneracraensucraroomnaancoern m-rae asno ae nausceermus,n w-eree croa-nasccrvaoornsa an co-ancuvcaeosrrea.ns.c,ron o,eenes,nvove.n-sc comex recrus aonaranscron comexasorme,e ranscr eeveomen.ncee osoraeeocnraceua ona co-acvaor recrusnaseso oc snanas anr eossmean,eano ase-eeneneraaon. moce an ceroenors na roeneeveomen o maure cesrom surace o– –.ne corca reon oemus,eoc receors one mc srom oue neave cero+enor+snerac w exresse on rmaroca- ces,enaernoeeveomen o oueosve ces.e eweeno acon necessaror ce erenaon aneveomensa can asonercac w an .,ou ceroenorsneracrmar w ,e n one emomena,ee a, anae, amon oeroc snan aonss. ,ae,ae, or a comonnason oeoc snanawa ma comrse , oc snanawa ma comrs ereo.n anoer emomen,e aons oe or a comnaonereo. e one or moreramens o , ,ae,ae, comrse a re n anoer emomen,e aons oeoc snanawa ma or a comnacoonmenraeno. ornu ansoonerro emeno commenr,sne r aenco omnen oan oru,sonr,ae,ae, an one o , ,ae, orae, an aramen o anmmoen ma comrse on-mn exames o suc recomnan oruson unoounroen. comrsne exraceuaroman roensncueoc snan aonss escren..u.o. o an. o.ra.o.use,o,e.cramen o as^ - - as ane anno emmc aoccmesesno,n o_as aro.e.nn a acnce esmsoon o_ ..n an emomen, o _ ..n an emomen, as am sen, as a m accesson _ .,_ ., or_ ..neco anna erroen accesson o seconar m accesson o_ .,_ ., omomen, as a emomen, as a seconarenomc acces r_ ..n an _ ..n an emomen, as a secosnoan o_ .,_ ., or momen. rroen accesson o ., e , ., ., ., ., or ..n an .,, as. a seconar m accesson o ., ., ..n an emom,en, .a,s a seconar.,e ., ., or ., ., ., or ..n anno emmco acmceesnson o ., accesson o ..n an emomen, as a se , as aroen , , or . conarroen accesson o , e erenaonece n o oneor c eemoromenenna o,n rs mea a o cnoewa m orr moonres ascvanroensanuce ce awa.n anoer e se an aons o a-ce receor snan oe momen,e aons oe snanawa ma comrse aan ma maorsocoma comex .ans encoe e areveno arene cnoaseses a,s causmsan moeecues orans an cass moecues orans.assocnumans omorcocneu enocreeu amnanenenome.-a,ss-an, asnnn-ra,c aenu aarre amone mos rome cosoorresenaono ces.asso eeserve , -, an -.ese moecues cnumans areenoe as - an oer secaze anen-resenn ces, wcs, arreesoeunne onees suorace oe cnerscor cesnaon o coneroucon or anoroucon vaeerun e oreveon cesororesso maure ces,ec mons. se-reacvosnuseween se an n us ex aeree o omc eea cesr on-se.nemus, ans one surace “ ” comexommaesuerne se-e ces.es coermsna a r ceoamc weexaerm we “eesee s-e-” or^ - - coomsveexe ses aerce soen.ece ceosruareor no reeraecn waon seo- or com cesn arocess cae a reacoo sron unero conaeeo exese neec, anose s conemaeneresenns acoososs va neave seecon. comrsn one or more ure,e comosonsescreeren, awae.. onuceoes encon one or more aonss oe snan ss , an cass or cass an, caneevereo a non-mcare coue weren ce erenaon canaeace ..nceaen u e cesramnsrasen,eae nnon-ome ecxarresesonss oue,ee on oene or moreonuceoes areranscre anor surace oearessue ce or more snanawa aonss one conac w ear s.rcuan cesa maassrou or oerwse mae surace o essue, manerac w e snan aonss exresse one ne oanreessue ces va,or exame,- neracons. soco emomen,e aons oe snanawa ma comrse a maor comrsma comex cassan.n anoer emomen,e cassan sensan-a,wa m-a, com-r,se or a anomoo cassereo.ann o.nne a enmooerm emeno,mee ano,nse oe cassann o mnae e cmomrse -, -, -, or aomooereo. ee- comexo orm anen,e aons oe snanawa mae a snec one aereeean. more cons ne osn oer emoonucmeeon,ee comosonsescreeren maurer comrse one or roero s encone one or more cones.onesa a cruca eveomuoueerenaon o ceroenorso ces.urn ear ce o ceerno,en-ors ano manananesnoo oe sucmc ce mscroorenuvrroenrmenerernomaoe raroeraon uono e a., namc nceroves ann a sa on aneveomen. moceroenors,aeo,,:-. e-secc manneroe eares roeneroeraon oemaooecr as asoeen oserveoa a an onumanemao oenor ces.aane e a.,u-eve eecs o ranuomonoccroenorsmoonoecss:c exreacnusrsoonrs o,uooa,ve se,m ces: anr-oer.ao-n os^ - - r ceomumreor exresson oeranscronacor , wcs necessaror neae nmeaene. caorce e a a.,nannramc cones, no ce anen receors, seces ,:-.nn comromnaoeosn weer-enaon o cooxc-neae ces,a.mmuno., ces. ,-s aso reureoreveomen o -,-,n o-ne, emom,e onr, a ceo omne onra moonre ceroeon.esn m anao coemr emrseom-e,n,e o,ne or man, conesnuce _ .,me ore n an e e oroxrmes _esno,n o-a.s. a. nr aone enm acocesmseonn, o_as a. m,_ acc ., _ .,_ .,_ ., or_ ..n an emeossmon o -as a seconarroen accesson o en, _ .,_ _ .,_ .,_ ., _ .,_ .,_ .,_ ., or _ ...,n_ an emo.m,en,-as a seconar m accesson o _ ., _ ._ .,_ .,_ ., e emmoommeenn,-as a seconareno,mc ac_cesson o.,_ or._ or_....nn a ann .,,-as a. s,econarroen accesson o ., ., ., ., .,., ., ., ., emomen,-as a secon ., ., or ..n an ., .,ar m., accesson. o, .., ., ., ., ., ., ., or ..,n an emo.m,en ., a seconarenomc accesson o . ,-as ., ., ., ,., or .,..n an e.m,ome., as aroen accesson o .n an emom n,- , en,-as a seconarroen accesson o _ n a.n, , e omr _omen., as aroen acces _ ..., son o _ ., _ ., or n a_n emome.n,,_ as a. m,_ accesson. o,^ - - __ ..,,__ ..,, or__ ..,_ .,_ ., accesson o _ .,_ .n an emomen, as a _ .,_ ., or_.,..n_ an em.,_ .,_ ., roen accesson o omen, as a seconar _ .,__ .,.,__ .,.,__ .,. or,__ ., n an emomen, as a seconar m acces .. _ .,_ ., son o _ ., _ .,_ . _ .,_ .,_ ., seconar ac , or_ ..n an emomen, as a _ .,cess_on o_.,.,__..,_ .,_ ., _ .,_ ., , _ ., _ ., n an _ .,_ ., or_ .. emom emeno,men,as a saesco an saerconrarenomc accesson o _ ..n an ., ., .o,en accesso.n, o ..,, .., .,, ..,, .,., , . .,., ., or., ..n., emomen, as a seconar m accesso an m., ., ., ., n o ., ., n an e ., ., ., or .. .,o ormen,..n ana esm ao secmonenar,enomacs a accersson o ., ., onuceo oen accesson o .. onuceoees e ce nos cmoons oonnes o arn mor mee acovsanescrroeenseraenn mucae co cemrseer oennea oorn m oore ces ursoeeneorer cne wse..,oc snanawa aonss, snan aonss, cones. roenees, an reeereen,c “ecororesoen renaoon”s oreween , c, , m, reersoe unernooca reaonsewee “nenceosen”euresenercaneaeren sene ar wou unersana oerave “corresonnn moo”e ccaunes.s suc, one eermneeosse unern anor resun seuences o oer moecuerescveenmoe^ - - s eexaumencee, oro amn a oer mo seecuueencea, anas a sm saerueonoceca reaons wese moecues.or seuence, a c seuence canee caneeermne, anrom an “nuceoe sse usueencee”ren c,a “noenneurcaeoerm reee”ne rus. oe an sercaneaeren w “nucec ac” an comnaons an reerso, am rn o aeaswoase-suar-osae o sne-anou on oers, sne-anoue-srane , as a mxure o sn e-srane reons, sne- anoue-srane , an as mxure sne-ser-a anneo our, me-osrreaneca re,onosu,e-rsra mnoeec oure as c momxurres on sne- an a mae reons.n aon,onuceoe as useeren ca anoue-srane reons comrsn or oro an .e srannsn re serore-srane e same moecue orromeren moecue uc reons canerom oe moecues,u morec s.e reons mancue a o one or more moecues o are-eca reaon,n ovoevne a onn o ao renuconeo o seo.m “eo onuec meooeceu”es a.nn “enu oce acs” aso encomasses suc cemca, enzmaca, or me ec onuceoes, as we ase cemcaorms o an aoca moeorms o ces,ncun sme an comex ces, caracersc o vruses an eren, cann ner aa.ornsance,eermonuceoe, as use us, sc ouressnc oruns u ansusueascraeses,e sruecn asa cnoonsanen, o onre m oor moere moaseases.raeases,o nameuswo exames, areonuce es, suc as “onuceoe,” “nuceoe seuenc oes aseerms useeren. acs,osorooaes, an oer veasr,”an ans o “nuceeco ascsa”e asaocncounee o nasvee nuceec nu accesc. oauarca nounceescu ac cosnaavne ae soamseaaesesa.counse, arsc oar nucesc w acs can conan oeres sa oror oer reasons are “nucec acs” acones moeor eren.s useeren, “nu or "onuceoes" asaermsnene. ac anonuceoe asceecn aec seuence” an “oonuceoe” aso encomasses a nucec essener m esewereeren.^ - - onuceone cser enacno exnamee o enme oor mmoerne asc ove comosonsescreeren,e one or more or more messe anroens anor cones ma comrse one moecuesnn a aner en ecmoeo onmm een or, m on m oeo re orec o mu coerse. m moecuesncue one or more m comnaonereo snanawas, one or more cones, or a m moecues.a enn acno eem onoe omr menor,e oneoc or s monrae mnaw maosec aunes oncue one or more n an emomen,e one or more m moe ne or more cones. encoe ,-, , or a cuesncue one or more m moecuesa mmoeocu comnaonereo.n an emomen,e one or more m e esncue one or more m moecuesa encoe ,-, an .n an amnen,-.e onn aen o erm moore mmen, meo oneecu ore msonrceu me one m or more m moecuesa encoe moecuesa encoe an .n a oecuesncue one or more mncue one or more n emomen,e one or more m moecues a m m moecuesa encoe- an . m mno cercaan eoxnasme emomens oe comosonsescreeren,e one or moremmunoeoneccue,s a mnaor commrrosvee ornaens ora moonre e mocenccaonsancrease m sa, reuce varousorons o an m moecu .ocaons mae maeo an oe a. e,ncune′-ca,e con seuence, ane′-o- ′-aoc emomenn, onee ea ′mo -caons mmaen c,omer osnee o onre m oorre m m moecues ma comrse a′-ca.n onemmunoenc, ano ore mocaonsancrease sa, reuce e m a rmroveeransaon ecenc oe m moecue.e′-en o ecenc.n esouanrowones a,see′-′-ccaa cosn essssesn oa a moro moeua-mne m-u sa an7ransaonasorme co-ranscrona ans aeoroe anosnem ca, wc nuceases.e m7saeoer ce m rom′-eneraaon ceuar orme mnma′-ca srucurems7ranscr,e w neurceeno ‘e’ v rae ares′—ens′rseorssaraensocrneo^ - - nouc weoce oe euea mroc.naeo′n-caacoar es a roennse ann reacron oransaon, servn ase senaeransaon oe encoeroe useransaona macneroransaon, omzne′-c n.vene roea′-caasn m sa an anao ca.n onen emeomen,aes o cnruec oar moorree msonnca eonesc covme mrse a m ve7cors. or m7ranscronan vroc ca mn ussn are comemneerraca ca avaea uesnacc onnea v orusw coa sraees:os- co-ranscrona can wenuceoe m7or n enz7mes, or a mae usen canncue,u are nomeo s anaos.naos o m m7-eae cas,osoroo , an-reverse ca anaos ,wo-moo ae cas,osoroseenoae cas,oranoosae cas, cas conasnnae ca′-s,, a′-nmoece nuuancoescne ac or′-eo cxa-s.-mesu aarneo msonenuceoencorrecncororaonno snec m ransc e7, wcreven sowno moreanoueransaon rs vae′-n m anaveeen ens e a.,ne ecences reaveo unmoe canuceoes. naos ss anroeres o msonanneove “n-reverse”a em-ee e a’-.,-movee “an-re an-me ’-eox , ,, ,- , , , verse” ca anaos w suerorransaonaroeres,ransaona ecencnc-ue.oe saurermrove m7sa an ave aernn an,oru e are nomeo,eraosae anaosm a r.em., ,, -, as w,eu asac eos a.,nec m an,esen. susce oe m oecan orooae. morueze anaosa reuce osorooae ca anaos sae m anncreas n-oasa, e a., ces, , , , - owasa, e aeransaona ecencn mammaan ca anaos conannosoro .,ness an caraceraon o moeecanroosaasoae susuonsan o e an are ressan osorooae ca anaosncreeasec sa, a, , , - un e a.,mmaureenrc ces an nransaona ecenc o vaccnesn ,-. ona monucaceo snuserooremm′-ucnae, renscounsensn vosveo, noeneescrerea,eren,u^ - - aerercesaenesc aerson sene ar, are aso conemae wne conex an scoe o coneuoesnucree.ocao a encoesn onee o enme oor mmoerne,n aces v oanen or mrooerens m a moecues comrse a con seuence comrse one or more m nor cones.e con seuence mamro ocaonsancrease sa, reucemmunoenc, anor oeve meran msoaecoune e mcaencae oeeo mrm o m nuoceecouse.e souscauoonnss aoe con seuence mocaon norosoeser nuceosens. su osneu emonomen,e one or more mocaons ma comrse one or more nuceosesne ms.u mcoeoecsuees s wus nuuconesos coemsrsae mncoue,nu or are re noacnm naura seuourne,1-me seuournem1,-ournes2,- e5o, -meaenosnem6,′--meurnem,′--mecmencnem, meaenosnem, an′--meuanosnem.uceos em,′-- m1aree mos we useor reucnemmuno e susuons w anncreasnransaona ece1enc o m moecues, as we as wc ac nc. an m cane useo reace urac-rc reonsn m, aumanv ea ae.,encancae anmmmunmeun soseenmcro ou unmnoeraeco ann wseuoou-re receors s. evere ssemaca w nanoarcesn vvo,omae ne-moe m usuons w an m1ave asoeen sownoncrea ras, ,,-. a.,ncororaon oseuour seransaon ecenc.aro e ncreaserans neno m esueroronmmunoencecor w - vaonn ea aa.,ac anoocaa,oecuareraeucs,, , eα-eenen -me-seuournen m nancesransaonrou esearc, anneenenecansmsncreasnosomeens,uceccs osoesner o, mneo emcao, omnse.n-,omme. o onneo or more mocaons ma comrse one or moreo,osorooae,o soeser mocaonsncue,u are nome mocaonsoe conra sneouenocse,anec,u anno′-se- nmoeescaroen meorencauo ans.recaeona a^ - - esrcsoonsu sene ar, are aso conemae wne conex an scoe oeresen or-e.aoc emomenn, onee emooa -mon aens m,ae one or more m moecues comrse ao-a.n one reucemmunoenc, anorm croomversee orannes or more mocaonsancrease sa, o-as a can o aenosne resuesocaea aon ee′c-eennc o oe me m mo meoceuceu,e.e conrueso m sa anransaona ecenc.o wc u are nomeo,e aon o′- caonsoeo-ancue aenosne,osorooae mocaoneoxrzaeeencosan eeasonown as corcen or-aza- m o areveneaena a.,osoeserocaonsn , , - , an on wouomromsnroenxresson, , uorescenceaen ouar aoc mon o s auoerooamneannaanucseers er aa.,ueovaen erormenvnes,uceccses nsaon ananeoeo-a,ncunos earc, , , e. ona mocaons ar, are aso conemae wne neo conesecxr aen sceoreen ou aerecae aerson sene n aono srucura mocao resenscosure. aenosn ns,eo-a ma comrse varousens o ,rome resoues.,nr oonme emoom,enro,meoo-a, e. m.a,, comrseromo,romo ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,,,,,,,,, ,,, , ,,,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,,,, ,,,,,,,, ,,, ,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,,,,,,,, ,,,, ,,,,,,,, ,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,^ - - ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,, ,,,,,,,,, aenosne ,,, eoon resues. enera, conon om onea emmon zaoomn reene,rseo a onero ocers ms oore moonunce ao nucesec ca ance se coueonnce oorm enzean.cen e axoruess,on,n,,e,os, ce,s o,n,ere,s or mo rree caoconns aeas one coone.., aou or morean morereuen or mosr oe nave seuence w coonsa are amno ac euen useneenes oaos ce we mananne nave amno ac. seouoennce.asarouesre snceecsesn e cxoon u asaarcuarasor ceran coons o aarcuar ecenc oransao eeween oransms oen correaes we on, amo n o messener m , wcs,nurn,eeveoeeenen arcuanrr oanseerrns,ero meroeecsu oes.e ceoroensomennancera onsa seeec aene asvana a o enera a reecon oe coons use mosreuennee sn ces caneaoreor omaene exresson ess.ccorn,enes oon usaeaes are rea avaae,or enxa amvee,n a orean “smooansesa one coaoana ose”m avzaaaon. a www.azusa.orcoon aneseaes cane aaen a num e . e a. “oon usaeauaeromene er o was.eeaamura, ear ”uc.cses rnaona seuenceaaases: sausore arcuar seuenceo .: .omuer aormsor coon omzn a aenacous,r e,x arere asssoon avna aaaer.cnu oanre eoms coem areen aso avaae, suc aseneore ,,,,,,, or more, or , one or more coonse..,,,, ac a coonsn aonuceoe seuence encon one or more amvnao anc.roens anor cones corresonsoe mosreuen use coonor aarcuar ssuee, oreanoneu,c aenoore su canece coe.onn o onem emzeomoren ex, are csosoonn-on am szeec secu ceencese a,^ - - s eexureesnsceon on amzuemano orr exumreasns coen,n or ao eur aanrooeer, e eu.a.,rouemans.e.,en omzeor mamma or avan assescre esewer , suc as anoer anmae.., a e am oe ornar se arsaeeren.uc coon-omze seuences are wn eonuceoes a coon-o nn vew oeescroneren.n one emomen, are nomeo, eea cesmnczeuor a secc cee.uc cees canncueu nn oeroow orans, ne n sn ces, cesnneasronesnarac, ces cese. rve cesnerves,ran ces, sna coumn ces, nerve suor musce ce. ass,r aonc sese,eaa m cuescs,e ccewsa,n cnon cneecs evec.,s msuues ccee cese.., carac musce, smoo ces,one ces,enon ces, carae ces,oo sa an oer sossueanmmune ssem ces,erm ces, a ces, sem ces an oerroenor ces, wne am oe or n comnaonsereo.uc coon-omze seuences are emomen,eonuceonear se arsann vew oeescroneren.n one canncueu are nomeos coon omzeor a seccssuee.ucssuees ss , muscessue, connecvessue, connecvessue, nervous suee, a anrs eanne vaews osue.eucesc crooonn-oeremnz.en s oeneue enmceos armee wn,neeo amnuce ooee osrnar omzeor a secc oran.uc oransncueu are nomeo, musc coon ver, seen,ran,uns, somac,ear,nes,aa es, sn,nesnes, oo vesses,oo, an comnaonse er,ancreas,aer,ro,one, am oe ornar se arsannreo.uc coon-omze seuences are wne n one emomen, aon vuceweo oe ceoenscr seuoennceer een. roens anor cones oe comosons an me ncon one or more acvan omzeor exressonnarcuar ces, suc osescreerens coon. ces maeose o orerverom asroaroc or euaroc ces.e euaroc meouman, or non-uman euar aoaer ocru anarm oar oanr msmam, smuca a ass aer meanmmsacu,ssnecu, e.n., muou nso ra, ra,o,vesoc, or non- e, . uman mamma orrmae. or moren one emomen,e comosons an meosescreeren ma comrse one veces meavere s veeecceesaosree oneevere os oe ca arcovaoneeroveenres a,n anoro croeneesv.eresen vverro^ - - anevoerrn r veavoe.xames oever vecesncue vecors, vruses, non-vra veces, an oer enseevsecrre veecren. reaesmen es,n accorance weresenscosure, ma comrsee vec sone..,ameer oessan mcronsm.n one emomen,eever veceess m maa co cmomrsresee areraeaesesmemnsenosno one osseassnanm.n one na enmomoeemrsenn,me.enver emomen,eever veces ma comrse areaesmenson oessa one nanomeersnm.n one emomen,eever veces ma comrseere n e..,ameer oessan nm,essan nm,essan nm,esaesmenson an nm,essan nm,essan nm,essan nm,essansannm nm,ess nm,essannm.n one emomen,eever veces ma com, oressan menson rannewe rseereaes n one emoemnen, nme anev nm. ever vece mae or co er veces ma comrsearces.or exame,e ameer n mrse nanoarcese..,arces wereaesmensone.., nomeoo,reaerannm.earces maerovenerenorms,ncunu as soarcese.., mea suc as sver,o,ron,anum, non-mea,- semeco snoucs,oroarmceress, m suaseensroensa ore,a ars wcees, a osr comrn saruocnusrereo.ea,eecrc, an n one emomen, nanoarces mae use ese.., core-searces. eren.nenera, a "nanoarce" ree oevere comosonsescre n ceranreerre emomen rso anarceavn aameer oessan nm. ameer o s, nanoarces oescosureave areaesmensone.., areaesmen nsmon or raenss.nn oewereerneerre nm em anomen nsm, n.anno oarercesre oerree esmcoosurmeenave nanoarces oescosureave areaesmenson o nm oress.n s, emomens, nanoarces oescosureaveereaesm oerreerre an nm. we arecaea reerence maeerenenson ranneween nmnercaneae, were arorae.ano oarces or nanoarces caneaeeuanumose are sm arces mae o semconucn maera ma asoe enereves occurs.uc n a enou ca su nmauanzaon o eecronc orman aens an maaneo ascaaeearorc sesm araer useuronsesomneecare asencasconossu asre.ruem ca-rsroers^ - - anano soar nacneos warc oense-avaeeenro manuca acnuree a one arrea wnroe sococe oeresenscosure. an arearcuar eecveor sazn emuso areermeanusarcesneraces an ac as so suraca ns.e can se-asseme a waero ec.sonea ursnce a c vaarreace orzaon ens. renncecunnu,es e...o,m cmaornaceecrznnu moroo,menson, , , aomcorce mcrosco ,namc e ssc aare eecron mcrosco ooeecron secrosco ,ower-ra racon ,oureerrnr ,-ra secrosco , marx-assseaseresoronon ansormnrare -, uravoe-vse secrosco,uzaonme-o- mass secromer manec resonance .ara aoarzaonnereromer an nucear arces. cerzaonmenson measuremens mae mae aso nave onuceoe.,esr eenocaonn o onre a ore mroorea acnva oner coareons anereonr caro reerso e.., one or more or an comnaonereo, an manc cones, one or more cones, arces o an oma szeo ue aona carrers anor excensorove resenscosure.n cerarnerveeerrreor a enmon vmreon,s e,x vavro,c aenormenn vsvoon ae.c.,aonam oee caracerzaonsase on measuremens usnnamcaser sc er o..aeno.,, ..aeno.,, ..aaeenrno.,.,eno.n.s mae o.,, aneaman e a.,n vv aen na o enoea s ever usnomerc on:oa.rcensna wow moecuar we,aureanoecnoo, ,, -, measuremeno..,escrnarces, meos o man an usnem, an ecorsn asner anor consoesree oco evo.r scres eeerem erns e anr.e vecorsa cane useoever an oeonuceoes ces, anrans e vecors cane useunroucnuman ces, anma escreeren.ence arn umseassorae c vaenc eoxrsr aenss o vneceo orr s msoerems comescornens oe comosons e scoe osscosure.nenera, an asescr eeren are aso wno aooa aows oraca e esewereeren,eerm “vecor” reers some conexs, wc we aesreceareanser oose an o en ornarrom s onen envero anrm,e “nvecoor a”no caner.en a^ - -ermas oe aernon reeer.o a v neuccoerc ca ance m ao reecuceo cna, sauce o asr aansasomrn, anaoe,er nucec aco wc anoer semen maensere so asorn aoue recaon or cosm,no wc enera, a vecors caae o recaon wen assoca oensere semen. ecorsncue,u are nomeo, nucee wc aceroer conro eemens. srane,oue-srane, oraraoue-srane n moecuesa are sne- one or moreree ens or noree ense ucec ac moecuesa comrse , oro an oer varees o.., crcuar nucec ac moecuesa comrse , “asm,” wc reerso a crc onuceoesnownne ar.nee o vecors a semens canensere, sucu aaroue-srane moecueno wc aona vecors a vra vecor, s sanar moecuar connecnues.noere o vecororacann woer aen v vraerve or seuences areresenne aenovruses, recaoneecveru asenoe.v.r,us rees,ro avnru asees,no r-eassoccaaoen veruesceve rerovruses, vecors asoncueonuceoes carre a vrusorransecon s s.ra vecors are caae o auonomous recaonn aos ce no aos ce.eran e..,acera vecorsavn aacera orn o recano wce arenrouce vecors.er vecorse.., non-esoma ma on an esoma mammaan o aos ce uonnrouconnoe mmaan vecors areneraenoeenome enome.oreover, ceran vec os ce, anere are recae aon weos e are oeravene.uors are caae orecne exresson oeneso wc ommon e c vecors are reerreoeren as “exresson vecors.” asms.xresson vecors o u n recomnan ecnues are oenneorm o escosureeconm anoarmn e sxuraesseonor ve ecxorress csaonn conm arsoes a c neuc.ec asc meaen.s., aaonuceoe o exresson vecorsncue one or more reuaor eeme e recomnan eos cesoe useor exresson, oer ns, wc cane seece oneass o exresse. n a recomnan exressaveneoe nucec ac seuenceoe are usenercaneaeren on vecor, “oerane” an “oeravene” eerm “oeran anurerene esewereeren.ne conex o a vecor, e reuaor eemenes”ns an meannneeroa m aeanowsaore ex nurcesesoone o seuee nnuccee ooneer seesusencneee.o.,^ - -ne anosn v cero.ranvsacnraoeonusra vnescaorosnn scsueeme onrvnr aos ce wene vecorsnrouceno o suc vencors ca uses an aeno-assocae vruses, anes emome n asoe seeceorarenarcuares o ces.ese an oer acsroncns o ve ocnoee r e v cmec anoors e um a sen en, vec or oeor ne ve s ocs roe mrm or cs ean are eemee e ascr nscesr eosnecw veerceore.renn. one emomen, one emomen, exresson o ee oe comosonsescreeren.n e romoer or o mens oe comosonsescreeren canerven escre er uuousromoer.eree eemen o an oe comosons romoer.nerens an m,s exresson canerven ao romoer, suc as a n o onnee e emmoommeenn,, aewo are comne. anor cones oe comos voencsore csacraee oereenv,e cranneo c ao cmeo osnee o or m oror ceonoannuceoes romoer oeraneo aonuceoe encon ars acvanro a mnma secon mnmaromoer oeraneo aonuceoe e en or cone an a or cone, wereneen oe vecor ncon a secon acvanroen onuceoe seuence seuence comrsne mnmaromoers an n ceran emomens,ses versas veacnor.s an.sn an an a eemnoo-assmoecna,ee v vreucor cane a vra vecor. vecor.n one emomen,ers reuaor ee s or an aenovrus emomen,e secon reuaor mens aomerase romoer.n one ese an oer vecors e aeremeunrse aomeraseromoer. eren rescreneans secon an esewere e.coreae vures oe vecor,eecoors cnauncneocuee aoeoneaveeareur,es a varu csan caornceer onre or moreunconaes oee exresseereo.uceauresncue ouceererom, or a seecae marers, moecua u are nomeo, reuaor eemens, e. w renerse.., moecuararcoes, sazn eemens, ane aonaeaeu aresrecncauee canosee sene onn suec aracaors aesesen c oocee o exreessoosn v ceecoro ane aranseorumaeo,reeevmeen os exressonesre, ec.^ - - canncuen on cee orra mno erme reoumaeonrs, eemeenosnuace coanees o aneraorv vecorsereoescreeren eerm “reuaor eemen”sneneoncueromeneoeonuceoe. enr ses , oer exresson oers, enancers,nerna rosoma asoaenaon snas ano- con seroue enecmesen, asne. ce.,uraanrscorcaoznaeornm snanaosn se.n.,as, sucocazaon snas.uc reuaor eemens areescre,or nucear eo,a. .euaor: exam eemensn ,e,canemoecere,ss,an nuceoe seuencen ma cueosearec consuve exresson o a seuence on nes oos ces anosearec exresson oe nuceoe romoer cannre ccer eaxnresosson cersmea.r.,snsu ae-sesercecs resueu oaorne sreuences.ssue-secc one, sn,oo, secc oranse.. es, suc as musce, neuron, euaor eem ,ver,ancreas, orarcuar ceese..,moces. cce-eenene onrs mevaeo asmoenraec s eaxer-eseseonnenn a memannoerra, w-ecenen manner, suc asn a ce- or ce-e secc.n one emomen, a veco ma or ma no asoessue ,,,,, or moreo ro r comrses one or moreo romoerse.., oromoers, one or moremooersr,o omnoe oerrs meo.re.,o,,r,om,o,er osr me.or.,e,o,,ro,m,o oerr more comnaonsereo.xames oo romoersncue,u are nom s, or romoers.xames ooromoersncueu are nomeo,e reo, an vrus romoeroona w e enancer,e ceorovraous sarcoma romoeroona we enancersee, e..,osar e a,emeaovrus e romoer,e rooae reucaseromoer,e-a,cn:r-omoer, osoceronase romoer, aneαromoer.so encomasse e,e “reuaor eemen” are enancer eemens, suc as enanc ermnue o -o.e.o., erse-’ semen se o.,.-, enancer anenron -nce,ewe.en exons an o ra -onroc.a.ca.c..,o. ,. . n one emomen,e reuaor seuence cane a reuaor seuence ..a.o.,,,,e c.on.ean.s ou w. escren o co. arencororae, an reneerrennaceonearenaenneur encareon.^ - - nro omneo eemrsoemenec,e vreocmoore cra,n conanro am monerm, oaromoer.n one emomen,e mnma romoersssue secc.n one r.n aurer emomen,e mnma romoers anon emomen,een oe vecoronuceoee mnma o exresusc aeooenu seceuoencee,ssee vsesan..ransaona cor canncue one or moreranscrona anor ene anorrannsaaoonn o reuea eonrco seeuernoceesn, en. a., cero.mno oneers e,areceranscron oe mae emoe.uae consuvero momen, a consuveromoer e ar anncue, moersor mammaan ces areeneranownn uae consuveurom aroee nromeo , , ,-α,-acn, , an .ne soracera ces,eas ces, anuna ces areeneranown or ex arre,s ssuoc as a-romoeroracera exresson an an acooeroenaseromoer romoer" renn e ornn seo eemas. roomomeerns,ae rerecuaoenre e exemreesnso cnan noe c aon resuuavee,romuoner a. "euae anor saa reuae manner, anncuesssue-secc emora romoers.euaeromoersncu ,ssue-reerre annuce emomen, cononaromoers canee co enmooneaoromroecer esx anressnonuc o aeoromnuoceeros.n one secc ce e, uner ceran envronmena conons, ano en a eveomen.uaessue seccromoers c rurn a secc sae o romoerse.. , ,annc,u ane,u are no,meo,ver secc e.., ,x,x,, carac seccromoer ancreac ceromoers -,v,,c,n,, ,,,c,acx, censrae. ea ne.r,v souns c sa ese sma e cer,omoers e..,, ,mmune ccromoers romoer, romoer, cre seccromoers,e.. , romoer, ,er, enoea omoer, uroena ce seccromoerse..sn, , ce sec ce seccromoerse.. ,uroen an emroncermaer ,c anro mmuosecrse cee..,c, ,necc,racur,, , , romoers areeneranow snecnce arrom anoe arree w..,nesme snco.e oersssusec aonsuroer. ce secc^ - - e.., aromnouecreaco ancvaoensaranroscmroerosn c oaneeoosnuvceeoneu ucone aconronaromoers w an acvae acvaor, or annucercomoun, oraeneracon or a neavecononanuc envronmena conon, or oer smuus reressor une reressor coneorno omoeerero.m.,o aorrosm reomeorveaes. r.e,nresusceere.n.,oun a ounoeromoer smuan reease oeromoer e r s a reressor cemca reressorromeromoer env eressor or remova o a envronmena conon, o ronmen.enucer cane a comoun, resonsve r oer smuus.us,nucecononaromoers caneemeraure,o an, an suoare. sumuae suncuc as ceceomncao,naooromcoa,er osrn ocuere, muoe acuar aens,o,e-n,e-,acromoer,a,c,ex,sromoer,srore nome ex, moer,awn, oene enxam ore, es an n oe exrormesoseorns. maa a ursenuce ana can aowor saoemora conros nomeo soun ener, e e aorm o ener.eorm o ener mancueu xames onuce ssemsneccuroemearnacecc rnaeanounc, ceemrocmao eenresre a-nno orreerm-a e,n semr. moecuewo-rranscron acvaons ssems , , ec., or nuca ssems ocrome, omans, or e ra crocrome., suc as a nuce secnsccr maonnnaer.ne ocnoer emomena,ere vcec coran caensnncuraens ocnre oro mna acvn a seuence- unncaornoensos.r,ovennerna,onaaenu,caono. ore oen , wc aenuce screaen emomens onuce nnroen e.., werese s an meos o use an cane aaeor use exame, cnem onncea es -mco reosur uame. een,rormanosoerns, or.e.n, wuceree exrees asonc caanone acevencun,ornucesene exresson.ouaon oene e o an exoenous cemca cemca-reresseromoer xresson can asoe oane ncun a emca- , were acaon oe cemca reressesene exresson. enzenen suuconaemroemoererscnceu saee,neurs aree noemere eo a,.,e mazenan-eromoesro, acv:ae-^ - - com,oeun mas uzese asrreo-memoeerrene-r-c,es, aneoa,c accova-e aromoroeronoc e eecroc oscoecnoocem:- acvae sacc ac.romoers wc ar a., anocs, suc aseraccne-nuce aneraccne-r e reuae oenene:- ..aenos.,,e arnesseromoersaz e a., eren ,, can asoe use e.ecaene oarr meorrse a onas cones oe comosoensoesncurceeoeerse ennc coanne oe oernae or mnoree ac,uvsaeno,ro orens anor moeoncue aonuceoea encoes ors a seecae oerwse onuceoe oroee.n one emomen, marer ora, wc cane a seecae marer canencororae eonuceoe encon aoee cone sucae se n aonuceoe encon an acvanroen anor amno acseweenee-c aane m-aerrmernuos oee aec, wvaennrarnoseane o,r csnoserneeoeweeenewo ae- anor-ermnus oe acvanroen or coneoee.n on or e seecae marer oras aonuceoearcoe or u e emomen, we arecaeaeonuceoe enconnue s muoecuarener . canencororaeno aonuceoe e c seecae marers oras escreerenn an arorae manneron acoown ex onrees osro mno ore coem seoecneanse o maree cromosonsecnues an meos areescre esewereeren an ora.uc o ornar sne arn vew osscosure. wensan arecae one eneranownne ar an a an suc seecae marers anas are uae seecae mraerneresneoe wne scoe osscosure. as cnnnroen , m anasncue,u are nomeo, anas, suc osa souzaonasaosennroen ,uaone--ranserase , cromaoraas suc asos seuc con assoreoxn ano , , an eoeas suc as-a,c-asn ooanonc amno acs, suc as -a enzmac mocaonsuc a ,-a an-aroenasa can aow secc reacon w s- orsonaon onase or cemca mocaonsuc as resrcon enzme or oer enzumoeres cceeanvcaeem saens, se anmeonrsa s eencmoenesroauc cosnaan^ - - sroevcneom recssn,an acme acann,sa onamerwcsne,eorxaccc conme,ouanssancun anocs, suc as, ,romcnosoranserase anee, neomcnosoranserase encoeroucsa are oerwseacnne recen c anor semensa marers anor semensa encoero ee.., enes, auxoroc enoc marers suc as-aacosa ucs wc cane rea enee.., roen , can se, uorescenroens suc asreenuorescen onuceoesa ca,eow , re ,ucerase, an ce suraceroenswo seuences nonerenveroaues oneux ora moosree n,ewrm seeru senecseso nro acee. u.,oneuxaoson o a resrcon enonucease or oer mon enzme, c or ace uon , - ans-as, an, seuencesa mae aemca, ec. eoease.., moecuarener , seuences reu moecuararcoe or unue meaona aowssencaon.er suareor a secc mocaone.., sne ar e marers we arecae ose o comosonse.eecsacree marers anas cane oeraneo one or more comonens oe so eren va suaener, suc as acne orcne serneners as sura aesn oerrs are uescore esew3ereer : or3:.er morearene m veoceore osr. vnec onoer s emseom cmaene nnn ,c.ueear onee or moreonuceoes encon one or encuene vecor or vecor ss n moe encononuceoes can exresse wn an em, suc as a vra vecor ssem, sucae areareeo secc ceosr, onssuees, v orruasnsa,r ecc.ens onero emuceo smuecn,aearee vrnus maorces cane onuceoes canencuene vecor or vecor ssem s e encon encone one or more acvanroens anor ucaeonuceoesncueearen moe an can cones oe comosonsescreeren emomen, su eareeo secc ces,ssues, orans, ec.n one omer,,ncor asan nocn m-voreacu cear erce.rs, ane caanree cnaa moee oa cranene aaeceoe carrere.., oronuceoes encone one or more ac carrer an an aace ssues, orans, ec. vanroens anor coneso secc ces,^ - - coon roens ansm ore cscaro oen ne e o ss oewec eeorr ceo omeren onu,ceeooesnuceoes encone one or more acvan emomen, one or mor sonsescreeren cane coon omze.n one escreere eonuceoes conanen a vecor“vecoronuceoes” e one or mona aren aono an oona coon omzeonuceoes encon c re acvanroens anor cones oe comosonsescreeren cane seouoenn oceomr ezne.anncee enxerare,ss coononn oemosza ceons r oeenrseroes aro rceessac o mon a nucec ac aou or morean aou,,,,,,,,,, or mor n aeas one coone.., w coonsa are morereuen or mosre e coons oe nave seuence mananne nave amno ac seuence.uen useneenes oaos ce we coons o aarcuar amno a arous seces ex arcuarasor ceran oen correae c.oonaserencesn coon usaeeween oransms eeveoese wenene ecenc oransaon o messener m , wcsnurn e avaa oar on, amon oerns,eroeres oe coonsenransae an sn a cesenercauar aranser moecues.ereomnance o seece ccorn,enes ca reecon oe coons use mosreuennee sness. omz neaoreor omaene exressonn aven oransmase on coon aaasae”o anv.aaooen a u wsawew.aazuessa. aorre rceoaon a avnaaesee,aore esx caamnee, a aaee “no a nounsae was.eeaamura,., e a. “oon usaeauaeromenernaon mer o aaases: sausoreear ”uc.cses.: .omuaer aor semuence coon omzn aarcuar seuenceor exressonn aarcuaros sor suc aseneoreaenacous,, are aso avaa ce are aso avaae, coonse..,,,,,,,,,,, or mo e.n one emomen, one or more more oe acvanroen re, or a coonsn a seuence encon one or arcuar amno ac.so cos oorn c usoaenens ceoarsre,s reoneresncoese m maoseoreuee onnn ueseea csoonenoomr a aaase avaae a :www.easenome.orcommuncoon_usae.s e seeconneas,enne m, oroon u zen ana,oem. ar :-.so coon asna ceannoaancsernac,uanm aeae a,n reeorewnrce,sa mnaeosoo.on usaanen:e–r.a anss w,ere aesn aoaoen,^ - - usea ce oonovna o.ans oen ces,orouraras a en a c,aunceeecencessnes.erenaann an a:an-eae osr,eoerconon on, e,ssueee v, oecror arnoen: ,u acne-o. or seu caence ceo.non on oe emmzoemoern e,x a croessonn a secc ce-s a seuence omzeor exressonn a euaroe, on omze seuence exressonn auman oruman ce, o e..,umans.e.,en omzeor mamma or avan a ror anoer euaroe, suc as anoer anmae.. a e am o ssescre esewereeren.uc coon omze seuences are wn onu e ornar se arsann vew oeescroneren.n one emomen,e mceoes coon omzeor a secc cee.uc cees canncue,u are no oereooo,w e oreanas, c neersve cnecusnnerv sesn, creans, c cees,s snnna coeumans creons,e nsnarac, cesnn asroces,a ces,cwann ces ec. , musce c erve suor cese.. an seea musce ces, c ese.. carac musce, smoo musce ces, ces,enon ce onnecvessue cesa an oer sossuean ces,one sse s, carae ces,oo ces, sem ces an oerroenor ces,mmune e amm ce os,eer omr cnears, s ane com arsnaanonns vewer oeo.eucesc crooonn oermenz.en s oeneu eemnces are wn onuceoes coon omzeor a seccssuee.ucssuees caomen,e nomeo, muscessue, connecvessue, connec nncue,u are ssue.uc coon omze seuenc vessue, nervousssue, an eea oeescroneren.n one es are wne am oe ornar se arsann vew oran.uc oransnc emomen,eonuceoes coon omzeor a seccuns ue,u are nomeo, musces, sn,nesnes,ver, seen,ran, an c,o smomnaaco,nseare,reon.eusc,a cooan oer,manzcerea ses,ueanceesr, are wro,nonee,oo vesses,oo, se arsann vew oe am oe ornar n one emomenes,cr aoneren. arcuar ces, suc vecoronuceoes coon omzeor exressonn ervero asroaroc or euaroc ces.e euaroc ces maeose o or uma m aarcuar oransm, suc as aan or a mamma,ncunu nomeo o,nv,e osro ncon,- ourm noann- euumaarno mea omrm anam oar orrm maame.ma asscusseeren, e.., mouse, ra, ra,^ - - ecoro ecnue.nens on vr eeu ecc morosn omesecnr,e one oerre mn cane consruce usn an suaerocess orecnnuueess c aannoer u ore suae recomnaon anor conn meos orec mseeoose ca vnecnocrsue,escure noermen.euoa,eo rseecomescnraeon anno.r. coanenn eusewcaeroeneo. . er suae meos an ecnues areescre enonuceasnre e o renn ce. o emnoonm seenu,e an vecor comrses one or morenseron ses, suc as a resrcon or morenseron sese.., aouce ora msoor reeearrne aoou as a, “c,o,nn,, s,e”,.,n, one, e omomen, one ses areocae usream anorownsream o o r morenseron vecor ne or more seuence eemens o one or more rsa. ec nrouceoeors ce casros,ra en.s.,uceono anu vcreao oresse aunoovrra coarncees.eescre eren, cane carosn vraarces cane accomse usn an sua os oacan e s usen s conexeren “rans e vra vecor or vecor ssems. nucec acs anorroens ucon” reersoerocess wcoren seuovraa arenrouceo a ce roaroe or euaroe a vra or cane exosercoe c.eseer..a,cna vnro,n ex a v vvroa, orarnc vevo or wseeureovera vrarce,e vraarcesnecse ce an everse carooe ce vara a orseuovraarce cane oona concenrae ro nsucon. ra an seuovraarces o a comoson conann vra anroo erxsoesuuroevoraaraer cceess. cann onee o emanoem aenn, a see vcruser e useoran cer ase vecorseseu arcme co o ce na asr. n “vra vecor” an as use erenn s conex reersoonuceoe vrus a cane caa oene o or m exorrees esenmen ansromac oraanse a uoon onnuec oero moere, e suecmen as o a onuceoes encon e one or more acvan roens anor co s e escre eren,no a vrusarce an roucn s nes o e comosons one or more oer vra vecorssuc asn a vra vecora ss vemrus.arrac vee wcoersn a unse s asoemnes ore wreo^ - - c caonmoene unses oorer coomucons vonrsaesacrrceeseorrene.veer v ora a vnecoorr c eaxnreesson o one or more ssemnvovn mue vecors.n one emomen, ssems ar o a vra vecor vecors canncreasee sae oese ssems.uae ncororan mue vra vecors,envra-ase veco vra vecors canncue rerovra-ase eene rs, aenovra-ase vecors, aeno assocae vecors,eer- vecors,nox avernuos-varase vecors, v aencors,sen-rarr a vernuosv-raase ve vcecorosr,s.eres smex vrus-ase vecors an vraarcesrouceererom areescr er emomens o vra e vra vecors are conureorou e esewereeren.n one emomen, sae oe ce recaonncomeen vraarcesormrove nse c sersems. or m an emomens,e vrus srucura comonen, wc cane encoe onencuoreno ann euncereo caessn. a vnra ce vreacnor em or voecmoren sss,e smuc, co ams wrseerse one or more casroens mue coes oerenroens,eever ssem canron a vra cas comrses roen or a mxure o sucroens.or exame, ve one or more oe same an ,usever ssems oescosure can com comrses casroens,,, more o , anor one or more o .cco rse one or more o , anor one or vrus wneam enovrae, suc arsna,eeresenscosures acaeo a vaenovrus, e..,ow avaenov novrus, e..,vne aaenovrus, asaenovruswcnc rus,caenovrus, e..,ureoncaenovrus, masae ues aenovruses suc as auman aenovruses, e..,uman enovnrovaeruss c,o annemaaeenov asru ws, e.n.,reo sscaoesunroev wrus.scuusss,o an vreurse on w ason aeenoam acaeo oeram memers.are-secc cas varans cane use orvrus on-mn examesncue cas varans seeceono cronc meoe seece. ces,uman ces,reas cancer ces, ces oun,ear,enouseuema meanoma ces, sem ce,oasoma ces, coronar arer rmaroass, ee, e..,unn e a,,urrennonnarmac enoea ces aneranoces. annoweene ar aso mocaons o aenoovorus,-.romeacnseren ,,,,,,,,,,, aews, “asse-en,c eo.r.,oraona oensn,e,, enovrusasroensor aaccneroac,”oarm,:- , as wnsen aos^ - - reasa aranre moaocaaornose on,es,ee saeereeorsoorne can w raesa no e oxeacne a moa se aenovrusa couerove on an aenovrus.n asoe vruses uc aareroen as we asoe vruses reae reaeo aenovrus menoneeren, mon aenovru o menone esewereeren,eeacnseren aso exermen s an , resecve, cane aeoose vruses wou unue aerovraao annromenvsrasceosure anenoweene ar. caacor ueroovra- veco ors caonco reers n co semuoesnece. o ces- macnnmumon cse-armcnna reeas wacan recaon anacan oe vecors, wc areen use s are sucenor eare ceoroveermanenransen oneraeeene oneresno eonuceoe an e exresson.uae rerovra vecorsor use w os or cone comonens oe comosonsescreeren canncuemease uon murneeuema vrusu,on aeeuema vrusa,man seme,u en.o.,euccenscce vrr eus a.,.,ruom.an:mmun-oecenc vrousann e a, a.,n. comro.na:onsereo ommnere e a.,ro.:- son - er e a.,.ro.: e a.,.ro.:-ranser ssem maereore-een on .eecon o a rerovraene exanneeoroensma oar ae reroovuruas coanne oea a ar ree eressue. ces.nceonroranoren enveoeroens, a are aeoransuce orn vra vecors are rerovra vecors eren. r ec non-vn ces an areescrenreaerea esewereransene, seucrovruas o cnan c aesroane c eenneeesre areon aecoweor coenenovnaru exresson oensere enesnoe mnvorucs aens areos co-mmoexc r ceerosv.rusveasnaaesa ove usne a s. aenvornec an exresser e a oransuce ornec non-vn ces aner a a aroac canncue ers, wc canncrease ecenc or ecac orou ocarouce vra vecorsncue,u are nomeo,uma con anever.uaeenvra vecors,enemmunoece nmmunoecenc vrus -aseenvra vrus -aseenvra venccors v,rusoone-ausreneeneuvaraem veacorrsu,s smoa-nmmu,nosena.cmeanec^ - - v vercusor,ovn-easmemuenneverac veenccor, v craursne ar-rasse-enceenvaras v vercuosr, an-uanseenvra anema -aseenvra vecor.n one emomen, an-aseen enecous cane use.n one emomen, a-aseenvra vecor s vra vecor ssem n one emomen,eenvra vecors an -saesme caennev urase v. ssem. vecorsaveeen useo meae exresson,ac ecor or vecor conexs, suc asor ocuareneerasee, e. an, anorevern oer anoer emomen,enoa,see, e..,n.,ea ea aa.a,n,enee : –.n eemer , wcescresenoa, an eunenecous anema vrus-:ase–eenvverrea venae a seurare vneaconrecao enxroerssese anreaomsaenc oroeens w eenoosrman o an ae a-nreosanas eeneraon.n oese vecorsescreneseucaons cane ae macuar eonuceoes encone one or more acvanroens an mooeor use w comosonsescreer r cones oe eneraonenn ovnera em vecoorme orenn. ve,coeenvra vecor or vecor ssemereo cane ars- aareoron r ssemereo.rs-eneraonenvra vecors can conan roense.. oeenvrusenome,ncunea anoenes, oer aona vra ere , - an oer accessorenese.., v, vrm vu, ne, an comnaons rsoen,e rreauoanoernvenraes veec.o.,rsa ca ann resour renv aes wroeu acsone oe vneru osanrerceseseweenes. o recaonn vvo, wc ma noe aroraeor somensance a cane caae n one emomen,eenvra vecor or vecor ssems ore areocaons. eneraonenvra vecor or vecor ssemereo.ec cane a secon- conan one or more accessor v on-eneraonenvra vecorso no vrusar ruenceacors ano no conan a comonens necessaror recceroucon one sameenvra vecor.s can resuneroucon o a eneraaoonn-enncovmraee vnec vorrsu.sn oarnec eem anomeuns,ncere saesceone- seaneera ooese ssems overrs- accessor vruenceacorse.., v, vr n vecoracs one or more eneraonenvra vecors m, vu, ne, an comnaonsereo.neers- necessaro exress anac, naoe s anoe sneucconeoeenenraoo an verunsvarrac vee.conr onnec eumeso ameena,urees^ - - e annveaoee anneseacna conna conme oonne onnes a vreec sor aneweee ennvweooeerroenen veecors wea,o, rev, on a secon vecor.eene oneres,sromoer, ..,- are conane a cane usen conuncon we oerwo ve acn s canencue on ar vecor enerae a recaon-ncomeen vru orsacan an enveoe vecorso eneraonenn ovnera em vecoorm oern ve,coer sesns emvarrace er v. eeoc.or orr- veecnoerra sosnemereo cane ar- ssemsereoavencrease sae overrs- envra vecors an vecor ssemsereoecause,or an secon-eneraonenvra vecors an eweenwo or mo exame,e varous comonens oe vraenome are sacea reeren vecorsu useoeern vroo mae vrusarces,e can e cannenewen a consuve acveromoersncue u-sream oes, an avnsrcue one or moreeeonsne’ o creae se-nacvan vecorsenvraueromoerenancer acv oe.n one emomen, ar-eneraon a vecor ssem canncue a vecorasma conanseonuceoe oneres onr m usreamromoera areane e’ an’s, wc can oonancue one “acoarenee veocnosrsre”sena cna onn ceo onrano on oe or meoresenoes rennvoervee vnecaocra sen-n aacovann ano a vrusarceasrouce e sseme..a,o, an rev an usreuceoe seuencese..romoersorve exresson oeeauresr am reuaor an an “enveoe vecor”a conans one or esen oneacan vecor, romoers.n ceran emomens more enveoeroenenes an usreameaswoacan veco ,er-eneraonenvra vecor ssem canncue a n one emorms,e wnea-oenresen on aeren vecorane revene. caneune aerne,e oe eseuoe annecv orrosm o aenvrusarce ereo.s useeren, nveoeroensncueneenvra vecor or ssem surace o a vraarc aen “aenvse nooe ar coaesn” orro “oeun.erorro eexanm” mee,an ensv aeoroee onr e oxueorsero ae ca comrseroens emeene enveoe oe vrus.n one emomen, ens vecor or vecor ssemereo canncue a - enveoeroen. - aenvra aacmeno an receor or an am memerresen on ao mse ceaes vrarers enocoss oe vraarce eos ce.ecause s exresse, a w wce^ - - v waree va ore ce os, c veraaers.cese erx sureassne enveeoe-ro eenveoeroen cannec orransuce a cea a useresresoenece ns canencororaease oneos ereoesc a vrusarceroucerom aenvra vecor or ssem roenreseeere e.n. a,na cnaanwanc eu ae.,oue acr.e noer.meo,en-e en,o meonouse vruns envse voe enveoeroenssee e..,orzono e a...ro. - orzonrus ..ro.:- orzono e a. o e a. roo ..enee.:- orzono e a. e.:-,:a-oon rorzono e a.enee.:-,orzono e a. a. oo.: - erovra enveoeroensee e..,rar-anean e a.. eneer.:- measuesa varuasramcoxorvoreusnsseceo er.o.,enusnsee ee e a...,n.rcoec.. e aer.., . - , raes vrus enveoeroens, enveoeroens,oa env : acuovrus enveoeroens,ovrus enveoer eoeroens, an o ,emaunn, neuramnoeans,eas an enveoeroens, comnaons se, roens onuenza vrus, an n oneere eom. ncorora omen,erosm oe resunenvraarce caneune e n ceareneesno aenvra vecor sucae cearenees are cxanr ceossnean on an een svueroacee oroeen resuansuesnevora a carce.n one emomen, aenvra vecor .rensoecno.:- enerearenroensee e..,ucoz e a. rerc e a..o e a..oao.e an n one emo.mener,. a s.:-. secc ce e cane -nen-meae aroacoareenvraarceso a :-,amr usesee e..,amoun-maneu e a..oecno.oen.envra vecor can coenz ean a o.nea.r ooe an s.ncn.-ees.cee.n v:aran- o.ne neasuer eamo smennse, a romosocuncormeuseo a cearenee ane same oreren n can conane oera oe snenuseo an enveoe envra vecor ecen,uson-comeen vrus enveoer roen, suc as ann- romeenvra vec oen.s can resunroucon o a vrusarce moecuarecroneroor onr veceo cer s-snemnaronecnuoese a sseuoneenenav carnusuanrccoen. as as^ - - a ceroaarce cnane avanaeousor use were surace-ncoma es can resrce use o, e.., n oene ees. no one or more omeoemnevnr,a a c voevcaoersn-esocnr-eormernenrooe cn-eear canencororae e vrusarcesee e..,asarane onuae a ceareneeo aenvra vecor ca n e a..c.eors o. .n one emomen, enaeeannncue an-ermn:a romoman onaroen ansareneeoe vrusarce va a cov or, wc can conuaee ce emomen,e roen caneus aenone.., asueon.n one nnecen anoruso eo an enveoeroen, wc can oonae veco n comeen vrus enveoeroen anncuen aenvra anr.en one em-omen,e: us : caneuseo a cearenee erenenvra vecor ase -enveonno coensrruoce cnan conesrnucco.roruarenn voruser same or a seccneraconeweene an : acaesrouconuc vorn, arces covaenunconaze we cearenee anus caae us secc ce-ease uon a seccneraconeweene oaren a exressnsnnarner.s aroac can cearenee an cesncoma es can re e avanaeousor use were surace- envra vescrocrsaev uesee oe, e.., cearenees. e. nscose asnereamenorarnson’ssease, see, en.,vra vaecenorsuavec aaono. an aenos. an . ucaono soeenscoseorereamen o ocuarseases, see e.., aen ran, see, e..,,s. .,envra vecors,ave asoeenscoseoreveroe ,aenucao annos. , , varanereo cane useoev aeno. .n oese ssems or a roens an ereonuceoes encone one or more acvan nor o cneo emneos ome comosonsescreereno a ce. asms.ranserasms ceann,e aeennervarear voemco vrar sousse ome canncue one or moreranser one or moreeauresa can wor w oer rerovra anorre vnecvorraa vcecoornsesn ane c sansenmcuae^ - - cnacnr,eaosre e oxram oeer,wmser eonvean sacee ex oresseo vnec oor anor vecor ssem,ncrease vraers, anornoe vraarce.uaeeaures eesrenseroe exresse anoracae are nomeo,’,’, a c,a onrenncuen aranserasm canncue,u e.., anoc ressanceenes, o recaonr, seecae marerenesrac,romoers, woocus, rev resonse eemen, c cenraourne oaenaon sna, orn,ce oarnsos-ranscrona reuaor eemen, n anoer emomen,oca ves,cuo ovrrusn, an comnaonsereo.envra vecorarces are conemae enveoeseuoe rerovra or assneoereucnsonanceresseeaer,c e..,enaenucaono. enus ans a causave aen o vescu er.oca vrussneescuovrussoaerom mesnrnaonear somasn mammas.oca vrus was orna aveeenenenrna,razrs, e an a.,m..e.es.:- , annecons e vescuovrusesanec rennaromnsecs, cae, anorses.an o suesnae are v mammasaveeensoaerom nauranece arroos, vnn ecor-orne.noeso vescuovruses are common amoneoe usua re rusura anreans wuenezrea-ee v srumseso amres. eneemcoc aan varuosra enovre-oaceureneconsnumans en ae amno aceve w -nana, an oenec comcoarrosoen sares. ene o vescuovruses sowsaoca vruss seroocas n oe enveoe reaeo, -nana srans amone vescuovrus ncrom,u mos cose :- anravassosaosa e a.,m..roes.coners e a.,m..e.es. .eoca vescuovrus enveoeseuoe rerovraa veceor. ene:- exame,envra, aarerovra,earerovra,a arces mancueor esonrerovra vecorarcesa mmarerovra,earerovra, an accessorroens a ma comrse rerovraa,o, anor one or more emomens,ean, ao,o acna a vcecsecsusoorvrurso eennvse aoreeenroverna. ann ceroranam emmaoremroevns oese emomen, a rerovra vecor can conan enconoeesor ra.n one vescuovrus enveoeroens sucae resun vra one or moreoca vescu orseuovraarces areoca eonvovrursa en vveecoorse,seeueor-eee.nenenovra vecors, an renovraecors^ - - aenovra vnec onoer c eamnoncmueen e,emee vnesc sourc canae ane aenovra vecor.n one emomen,e ssemereo cane sero vrusarcerouce usne vecor or evere vae aen e or seroe.n one emomen,eonuceoeoe aenovra vecor cannocvurae aarce caonnuec ueooe aooueev.ereus,an ca onne ran emeon smzeen,r an aou. o aou .enovra vecorsaveeen use successu om see e..,eramao e a..ance.:- a e a. n severa conexs oe e a., .um.ene.er.:- ana e a...ae..enoe..::- . - ereo.ense on aree e amsoo remeerrne,oe vnecoer a cran ase “ aueeer-eenen aenovra vecor or ssem eneraon o aenovra ve ss” or “ue” vecors an are a moe emomens oeeer-ecoernsesnee a ee.n.o,vrara vseceror e s as.em on.e veacuorre.e:ee-r. cn ceran ae vraenes reureor recaonu conans a con an conan oman.e secon vecor oe ssem can c onaeneeecneacan moreonuceoes en onan one ens oe vraenome, one or comoson cone one or more acvanroens anor cones oe seecveacsaeescr reeeaseerreomn, ane cees nsaeev ee..,acaecnan re eco an.on. snan, wce can aow .eer-eenen aenovra vecor ssemsaveeen succ .:- severa conexssee e..,mone e a.. essuoreneevern a..n e.:- rane e a.mo.ceenneeeer.r.::-- ecan e .eneer.:- roe e a.. a e a. .ro. eneer.:- maano e a.. escre:ne-se anorra e a...: - .eecnues an vecors enco ucaons cane aaeorncuson anever oeonuceoes eren.nn onee e omneo orm meonre, acevoannucerooeneso aneoer cveroen veas oe ver comosonsescre aeer-eenen aenovra vecor or sse aarceroucerom emomenan aenovra veco mereo cane uo aou .us,n onen szerom ao r canncue a onuceoeoeeverea can rane er.u.:u.. o aou see e..,osewe e a...ene.nr.ene^ - - aenovra vnec onoers e amreo commeonse, oe veceors aransruc-aoenn eovrcae vecor or ssemereo.r vecor aneon-ermenome-ner nc o aene-eee aenovraenvrus, anr anoena o aeno-assocae, rerovruses, can resun saaensraonssonucaosen a-nenemraensenr.enra onoen e sme.oeme ee.n, suc r vecor ssems :- orra e a..um.eneer.:- u.,o aanauea en a...oo. : - an e a..one. e ano ..ro. :-, woseec one e a..o.er. use weonuceoesn enuceos ann veec oonres ores mcorree acvearenn carnoeen mso anoer c ano anaeseor comosonsescreeren.n one emomen, ar-aenovra oe moreeaures o a rerovrus anor a vecor canncue one or aenovra vecor canncue one or mnor aeeenaou-aressso oca ae su vmrau rse.rnov ornues e omromen,er- e..,rar e a..o.er.:- anu e a..o.oamer. vru:s.ee woseecnues an vecorsescreeren cane moe an aaeo -, onuceoes encone one or more acvanroens an r use we escreeren.vanaes o usn one o or cones oe comosons vecor or ssemere r moreeauresromesner-aenovra aroa ra o canncuee a oe vraarcesrouceereromonecoerssnneu oes cceens, anoanr-evacna cne csa.aece as aos e c.om.,arrearo o ee ar rerovruses, ane a anu e a..o.er.:-, woseecnues an. vec.oro.er.:- cane moe an aaeor use weonuceoes encon sescreeren roens anor cones oe comosonses e one or more acvan ceno-ssocaer creeren. n an emomaen,e vececoors es e a. r cane an aeno-assocae vrus vecor.ee, e.., eneera,ro:o-:- anuz.cz.a,a..o.n.,nv, on,umano aenovra vecorsn some oereaures, ses.: .ou smar anoraoenc anus cane sae ave someecencner recaon canneraeno a secc se on cromorsomane ae ono avruam vaenc coers. wn o nnoe o emseorvameen s,e eeecs.^ - - un oone a emouo.men,e caac oe vecor, ssemereo, anor arces cane o wne emomee. n,e r veecuoaro orr s msoemecueesre coan caennrocmuoeer osn,e en ora mncoerres, re reuraesosrors m aonecuees.en, sscem areereeoscr canencnureea oenre oera mo eresewoenrueceeorene.n one emomen,e vecor or roens.n one emome sa can encoe one or more reuaor e,e, n,e one or more reuaorroens cane seecerome, ee, v vecaroarn osr sesreeom, an comnaonsereo. encoe one ereo canncue one or moreonuceoesa can comnaon osr meorreeo c.ase carosens.roeen csa casnero caeans cea on aess seemecenrnomo a,,, an vrusarce.n one emomen,e cas can conan roen se oe emomen,e rao o :: n a cas cane aou: casroens.n one aenovrusne oneer eamcoorsm oren,oneuceoe vsecoar o cran s esnecmoee oreo: c.anncue one or more acors.uc aenovruseerac ne or more aenovruseer an s.n one emomenor,s a canncue,u are nome,,,, , aenovrusee roucnos cene exresses one or more oe a secc seroerac e.n voer ocs. noer e omr sosemmen,ereoe s cearnoee co cnanuereo-ro,uce arcesavn -, -, -, - or an comnaonsereo.n one emo-m,en-, -, eearo,e ce-s,oe-ar ore aen c eo.m., onnae co ,e can r ann seereeoc.ne c saenro seeecs,e, or o aer c w -, -, - or an comnaonereoorarenran anor neuro as one can seec -oraren caracssue an one ca na ces an ver.us,n one emomen, an vecor or n seec oreveroe arces caae oareneran anor n ssemereo caae oroucn arcesavn seroes eurona ces cane conureoenerae ereo.n one emomen,, or ar cas -, -, - or an comnaon caae oaren carac, asnsue can veec coorn or surseemoeerneeora cea aane oraoruccenavn anarces-^ - - a srercoes cea.an oen oe emaroenmene, anver can veec coorn oru sresemoenereo caae oroucn seroe.n one emomen,e vecors ar erae an avn an - s are sancueenomes w eemen vecor or ssemereo.r caserverom aeas o srom one seroea areacaeno a rouce, an erouneeren seroe.or exame,se r asoe scusse aove,escasmon m aenoesraseas omneee aeern-oreee,rearnsaesnmran wsecoen mee samo asscusseor r roucon.owever,e seconasm,ee e nsasm, caeea,eeenes serverom ,a w weeeaeren.serverom .eroucon scemese same ase aove-m ene roucon.e resun r s cae r ,n wceenenoone aroacor recomnan , wee cassase on .s assumee mesase on sae s r v ce orssue-rosm aua rus souee same asa o . a,.ro.: -on o ceran, wc sesro recaesu asaoenesea cees caenowe.ounnrmm,. e ene - - -ae- - - - - ^ - - vecor, smnar onoe emaoesmcrene,ne connec veocno wr or s a rseermereos conure as a “uess” “uess” vecor or sse ovra vecor.n one emomen,e enome a mereo canavee cs-acn vra eemensnvoven eonmuceocaeson e anncoancaen onne onra meor we acveaeneroroooeuns seuences onerese.., comoson s anor cones oe ns oensec ermeoemren. ru en,e vecors areroucennnsec ces, e..,ooera urcaesrearomn csoemcm ceercs,ar vownn serum-ree susenson cuure.erum-reensec ces cane onsrucon o receonmorsn,a en..,m vaecorrc - .ncun..a.o.,, rascn ssescren a numer oucaons, e a.,o.e.o.:- eer am.,onao.eu.zo.:- rascn, a unse aanmuosr a ea ae.,.or croon.sru:cn a-n or o.ern vec ooreczeca,nues an:or m-eos cane scusse esewereeren. escreeren. n vecors are eres ssemerenm o o.nee exmroa ssme emecno s,rs cane vneccuore cane aeresmexra -ase vecor or wc are comose o acor esaenecons sne co vruses,sroaaen comeme oeneecve muan enome.eneeecve suseuen cesermanennn re cecas,n vruserar owcnese cnaonmeeeune arraee noa are caae onecnnecousarces.ee e.., .rore. caae oroucn moreecnues an vecorsescreeren x.n.o.er.:-, wose oe comosonsescreeren.n o cnane eme moomeen a,n w aerea aneor u vseec wor or ses coemmoneenss uze,eos ce cane a comemenn ce.n one emome reo ereo cane caae oroucn vrusarce n, vecor or ssem uo . -ase vecors a s caae oevern aonuceoe caro o cone n ssemsereoaveeen successu usen severa oexcsnon.cu:n- varousa mroe.s o n.euroo.oco.sor:ers.-ee e.a.,aoacnr aen e a....eone.^ - - er.:-- anone ec ae.n an.uam..en..er.ur.:-zzouz e a..eruosc.ecn r.n.euro.:-, wose oe cuoems aons voecorsescreeren cane moe an aaeor use we comonens eoxvrusnsescreeren. emomenn, oenc eeo ersmoxovrumsen ve,coer v ceacor cane aoxvrus vecor or ssemereo.n one onuceoes encone one or morne a rcesvuann croeonsa asmncor e cxroessneosn o oe o cne or more escreeren.n one emomen,e caac o aox omosons aou or vrus vecor or ssemereo cane ru msorae. erovrarorcerouconromraecors o a suaen c oene emuc neoon ormerno,u ocneo onr o mo vreru vsraa vrecceosrs c aonor ssemereo caneevere aoaoeevereo aos ce.uae nanneonuceoe or oer an ssemsereoescreeren arenownosn cees aror an vru asre croomumceorcnarom av vra vecors exame, suaeos cesncue ces ans varans aae.or ces.n one emomen,e suaeos ceor vrusrouco an er,e aoneosrcreeren can s nrom vra vecors an ssems a a exress one or moreenesnvovenacane..,o, n one- em anoomre on,e ar seurornenes. or o ever o one or more vra vecorsoe suaeos ces arorr varuesenrouc oonmeromo a voraw voerc vorrsa anene s esemsereo,e ces arencuaeor an onuceoeoeever xressonrome vecors,acan oe roe ee..,eonuceoes encone one or more acvan secrenosn a on mora cureo vnruess oarcee csomnooseo cnsescreeren, an vrusarce assem, an areeneran uure mea.arous oer meos anecnues auorwe vnrousoasrec oes or cannare c sne ar. one emomen,s cannvove cenoruecaeonromo coen ccuenurraee meea vru as s.uaee meer oo.ne^ - - c moemooss coann conncaunenranes coucence a v surusaaer cces cane oane usn a suae meo.ucransucon ecenc,necvna enee.., ces aneermnn -ase meos,ow com cene a suae meo.uae meosncue meos anecnues areeneraer,no awnn aonosoe oc o sreencaron s-asen mee aro.s.e caornous oer o vrusarce cane ause as neee.n one emo cenraon conann vrusarces can c1 20men,e resun comoson envruses maeonraenarerom - anenavrrcaesm. eren.n one exame emo vecor or vecor ssemescre asmac men, aer connas wc conans aenvraranser conuenceeonea,eo aowassae= cane seeen a-aso anocs.er oureranseconn w eaovne serum an wouransecon rs,e mea cane caneo serum-ree mea anenvrara onsereenasmvra vecasors can aonneeo aursroaerra.eeasc caanneranassmeces we. o rr. -seuoe, an.u os ao ., o ca reva.ransecon cane ue ouus rneame w a caonc ever aenu oecamne an eaovne serunm..eseer meouorss, caen m usee saer cuamneur cnan cee cou aunre,ouc s-erreue w reerre. m-ree meos are cesoacoaoew annrraonsueccon an aowneroucn cesaso reerreo asacan ure.n an exemar eme vorumsenar, vcreuss w-conaancnae su cearrnaoa,nse ceanvraarces cane ours.oece vrus-conann suernaa nearvese aer .umowroennn ens canrse ceare oers anererou a a, rm.e re r.e canene sunn an uracenrueorours overn ae sun vrus-conannees cane resusenenu o a -er rees.e caneen auoe an usemmeae ormmeaerozen aeresceor sorae. ssemsereoere, s aurr ceouwc asoo mn oasne sersacereesoerrerno, wucnceena ornceoswrome aenov verucsorse aner^ - - aacrocrses areromrove veceoresr a vn. seseermrseee.reno o cnaen emncouem aenen,o a meo oroucn a saaror recaon an cas encononuvrusneconno cenes conanneonuceoeoeacae anevereceeoes aon w vecor eonuceoes encone one or more acvan resun arcee.., comosonsescreeren.n one emom roens anor cones oe vecors an ssemsereo cane en, a meo oroucn arcesrom o an aroraero a “eerree” meo, wcncues co-ransecon a conans aonuucceno cee onen weresree.e. v,eceorsoe.n.u,ceaosmes v eenccoorsn: aen one or v mecor acvanroens anor cones oe comosonsescreerene ore vecora carrese e-a encononuceoes aneerowenen s a o sne ar w arecae varous meos an varaonse uceoes.ne eerree an as we aseeren avanaes o e reoa areoeer an - on- ac ssem. “non-vra vnec oonre” er ama noec amoersn,e vecors a non-vra vecor or vecor ssem.eerm o ar are vecorsua are nos usaesee orne onnen or mso croen coexm roeneernsso o m ao vercues anor comosonsa an nuceoeoeevere anor exres us or vrusenomeexcunncororan one or more se e non-vra vecora cane caae o s caanncouneu,c weoouesom aa ceo on a,nnu naoc ere eoxorees nss o ucne eoe co esom annouscoeoons nuceessc eonre een coeer n-.en vo ann-vrae vveecronrs an vecor ssem raase vecor ae canencuno e onn aeus s ec. ameo naoe emseon,n ounce oeor moer.eoeenrumc oeo are “sn oaee coomnuocseoonse”e ascsr useeeren reersoonuceoesa are no assocae w anoer moecu eren oer moecuesa can oeneroecrom ee..,roens,s, anor useeren, assocae envronmenaacors anoreraaon.s encosen, en wncues,us nomeo,neo, aereo, asoreo, one or more ocoeseonn ourc weone,s mexsecr we,e arnen ceanee.eaveereorneucceoo aesosa cencu ane^ - - omoennsaona ex corensseuraeornesn..e w naae o noon-numceon eexsa cmanesa,ve na ane suoanuewo- anree- sne-srane moecues,oue srane moecues, crc ceoes cane arca cromosomes, moecuesa co uar moecuese..,asms an areoue sranee.., ro nanoronsa are sne srane anoronsa conans one one o zmes, anee.n one emomen,e naeonuceoe con r moreonuceoes encone one or more acvanroens anor a es.n one emomen,e naeonuceoe can conan oeronuceoesn oonn-oraeoonnuucceeooees oee comosonsescreeren. eren canne onnecu emeonm aen no,n oc -vnoer ra osr moorneuc oeooenu vceceoor.esu oaee n coonm-vosonsescre vecorsncue,u are nomeo,ransoson vecors an raonuceoe arca cromosomes,eas arca cr vecor ssems,asms,acera mnasms, crcuar c omosomes,anoc ressance-reeasms an covaen cose vecorosva“enum ceose sa vecorse.. mncrces, mnvecors, mnnos,,near ene e”, mnmascmmunoocaene asm exs,resso snse vmecsorso,s-sereamoncaro-nearn v secsoerms v,ecors,oenrasorrn res,res msn-nronc asms, anee.ee e.., orraon n one emom aree e a..enes.:. o recaon en,e non-vraonuceoe vecor canave a conona orn one emom.enn, onee e nmono-vmraeno,neu ncoeno-vrae veoconru ccaenoavee v aec morn cmanaes acnmmunasm.n eneene exresson.n one emomen,e non-vraonuceoe ooca moreos-sereaona n ssemenes.n one e vecor canave one or vecors-ree.n one emomen,e n momen,e non-vraonuceoe emomen,e non-v on-vraonuceoe vecors a mnvecor.n one emomen,e non-vrraaoonnuucceeooee v veeccoorr cnacnunecsu ae nu ocneea orr mocoarezaon m sonas..nn o onne emomen,e non-vraonuceoe vecors canncue one or more e aacmen reons s.ee e..,rovc e a..e.:- sc,aoonm ear ax. sco.surev..ene.s: are--,r wcos seeeucenncesuesa an vaeco ars r coaenne aae seaoar us oernanzearoense on^ - - c corsoemooso rmeeusaororu eemenso soucas aes araocmmoeerns,o enean ncuecrse,a arn ma orrx.nss are oenoun ncuson o one or s canacae a once-er-ce-cce reca o recaon. vraonuceoe vecor as an esomenauer ces.n c ono manane non- seuencesocaeownsream o an acveranscre eran emomens,e onuceoes encone acvanroens a onuceoee.., one or more oe erenncuene non-vraonuceoenor cones oe comosonsescre romeea-nereronene cuser.e veecor.n one emomen,e cane a :e u e a..c.naec.: e.-.,erne ese a e. a..:.u-ceccoraes. a..v.x.e.o.:- anesen e a a e :-, woseecnue ..eneer.o.o. n one emomens, an vecors cane aaeor useneresenscosure. useeren, e non-vra vecors aransoson vecor or ssemereo.s seuencea “sra cnasaoseon o” maosvon reeorrrmeocoa asonrann asoesnaomee eoem aneoner r.eersereo ar aonuceoe oransosons.ransosonsncue reroransos e severa casses reureeranscron oeonuce ons an ransosons.eroransosons eonuceoeo a newenomoeas moveorransosen oreroransose reure reverseransc e oronuceoe. ransosons areoseao noransoseeonucreoon oeonuceoeas moveorransosen orero vraonuceoe veo a newenome oronuceoe.n one emomen,e non- reroransoson vecorneccoures canoneer amn rearo reraenasso.sonn on veec emor.onme onn,e eem reoromraenns,e vecoroes noncueonermna reeas.n one emomen,e non- oson vecor cane a ransoson vecor. ransoson vecors vraonuceoe seuence encon aransosase.n one emome canncue aonuceoe non-auonomousransoson n,eransoson vecors conure as a ons own.n one emomen ve,coer,r manesanonson vaecoerarcanss oonse oorn moorees noon oucccuero soen seanueeous enconroens reureorransoson.n one emomen,e non-a nces vecorsac uonomousransoson n on oene or em moorec eemens. rsonuceoe vecomrena, c ao nnona-nvsraeo onen ourc meooreeorannsucoseoon veesc eonrc sosnem caen acncvuaen a^ - -nrvoeernes a reneoars cosne asne asc sercoeneorennucaenoe one’ an’ ensransosonermna o encon aransosase coueo aromoeroer vveec eoxrreassnocnu oese araonsnouscaesoe.e ceaae are exressene same ceeransosase cane exre noransosee maeraewe sserome secon vecor an can osonsneos ce’senenomee.n onse o enmoemrsen v,eceorra annsonsoenr vaeecor ono one or more cane conure as aenera.n one emomen r ssemereo sce acceor seoowe a r ,es cane conureoan a sronransoson occurs we usnse veocreorr o anr sosre omerereeone, aner aan ssroonsono cannsa.ennron o aene anensere reorer or oerene c erno an a resu,nacvaese anrovoe a ms-scnrocess an, as canncue,nu s aurea noemrraanse eosoo,nen se. eesenm caenae use.uaeransoson an ssemsereo see e..,vcs e a uransoson ssemcmarner sueram a. :..-e. an:-usa e, a.ac. ac sueramsee e.., e sueram ,rorncecmarner sueramsee e..., : - ,o ces. :- an va se e a. ucec on-raeverec ransereo. veces caaeee overev veerncees nsu mceac c aocmsr asne noorn-vrorae veces.nenera, meos an onuceoes anor cones oe com ns mae useoreverne vecesncue na osonsescreeren.xames o non-vra nanoarces, sreosnno,a mrucesu,n cceo-naen eenrvaeone-ee neasnoevcse,s nasn,ocews,o mesoorous scaarces, an oernoranc nano -coae a ar arces. osomes.ece oes ecveorn vseecscers mean co em..,rse..arces, e.., nanoarces s an anoecon reaens are so commerc a.os.,,,,, an,, an neura sa are suaeor ecean recee..,or-rraencsoecnamon™ anoecoone ocno™n.uceaoonecs^ - -nceuereoasrae oone oner,n:neurncaeocna acae cnomuexceas,onncuos. an .mmuno comexes,s we naree osomes suc as :- nowno one o sne arsee, e..,rsa,cence em.:- aesee em a., e aan.,ceroceonneuaere.:em-.:- er e a.a,o eoc aon.,ueane era:- ma e a.,ance e ,,,, res.:- ..a.os. ,,. ,,,,,,,,,,,,,,,,,,,, an anoarces an maeesv merae eonc caessus wae nu recaecve ac eas wn caonc arcese..,osomes, conan an vra comonens, wces mnsme.zne s saomee e axnammmesu,noe nanoarceso no arces mae useorn vro, ex v nc concerns. varo vo, ann vvoeveres. arces mae useor onuusc secoaeses o enc coenouea onoen osr. mnor some exames. s mae useoreverne escreer e acvanroens anor cones oe comosons meammoe omn. nuomne-nrsoanne sn ma, c,o-mrnsoee coaxo-n-c, s,- neo-- n ,,-noeoxeo-,-me--amn -meamnoroane noe---meamnoe-,-oxoan oroane n- ,,- meoxoeeneco succno-,e-mrson- , - o-"- ro-meox-oeeneco caramo- -sn-co -- ,-- ,earacona-,,,-er ,-mrsoxro--amne -- ,-roxu azan aen----meamnouanoae n-- eaecan---- e sexane-,- s-execanoae - , an an comnaonereroox.erearao-nox oo--uns aenc eonxcasuexao amno ocanoae-, e a,oecuarera, vo., no n mae aaeromosn n exame emomens,.e,aess--, s,eee ec.. era -uceccs ,,– ..,..asse, e a.,oecuar –. an.erraresso, e a.,o.armaceucs ,,^ - - nucec acna ocneo enmeoomsena,eseo ca conans a nucec ac, werene care rao o n one emomen,e o ansocncu nesro a sene aomns csom aoouun:, w. –c osr r aemoou:. rome comoson unern vvo conons.n on vaes aoocaner comou e emomen,e sen comoun care ons surace or onen m.oencu onee a esm suco.men,e sen comounoes no carr an oeencoe n one emomen,e sen comouns are sarco s a s,roxe ucose aseomers,o roxe mooromenen noroene.n one emomen,e , ,o , an a e e we eween aou o, a oreween aou o a.n one n, onee s emeonm ceonm,oeuns canncue o orne or more.eers.n one emomen, aeoueer mo caone m aoos ooreoa or a se croone.nn o one eem comomen,eeer seween eer comonensewee oson.n one emomen,e .n one emomen, n aou moo mo oeoa conen oe eoa c e ncuess a mo aneeer a mo o ucaonoseo .rn neonn- omen, e.xe,mar e,ver veces are,escren..aen e a.,.onroeeas ,an ,ov., e, oume,.- ınou e a.,omaerc., :- : e .oa:n. e a.,our, :-arc, an e a.,one, a.,euraee na.one. . eoecon ,ov., aea e ,e. nes. :-,a an e a.,v.eacareaer.,:- .ama anan e a.,newemn n., :-,ar., ames anc,eo:n. ananrnmaneno.arn.es e ao.eaou ere a.,anoencnooe u:se- onneeu e aa., :r-es.,an.:,c-ueesc e. a,.,.,n.rumncoer., e a.,:n..n.armaco.er., ern e a.,o.er., :- r., ovoran- ec., , an uceccs , eo:. mna.. seva,oecuarera–^ - - ,, ,, ,, ,,,,,,,,,,,, an,,,, a,, a.os an . nuroean c osom srucures cnes om oneos eemo om ae unn,- a or muarce maeosome.osomes are serca vesce comarmens an a reavemermeaamee oaureroaecr surorsounnnerna aueous emomen,osomes areocom o aer.n one ru moe ae, nonoxc, canevero roc anoc acrossocouecsa, mroeecer caroromeraaon asma enzmes, anransoreroa osome mao csoommem rss cr eaannes nae a ur mn aaee osromoo o sevrea sranarr aneerrens suce.s o s, e..,osos. osa cone , sn as,-searor-sn-cero- - or an com omen, e osacones, monosaoanose, anroereen sva .eroan or oe nser areo n a. ce,voesso mmaes mea auereor comosomesn orero mo er srucure,-oeo-sn-cero--osoeanoamne r,s ee. c.,ooesenrcore,a snomen, anor reveneeaae oeosomanne se sa anoro ar asn ooneec eumaromerno,aneosoor rsm ca eer s c,aon. seee aro e.an.,ors cesroosoocmoes.casso.nownne .ro .on,eeacns o wc cane ae orconen anorevereonuceoe anor aaeoenerae eren. anor cone comonens oe comosonsescre necooer n,on,-m-n, exemaran eosomes caneose as seornan e a., avarro,ourna oruever, v a., , - uc an o:. o. ,ar.ceo.,,, aes, . a comnaon o oecn .. , an ,oe.case,. , ...e..,.^ - - eerans,, ,oecn.ea.ce,nces,os-er,nvaou.x, aneraueeucs,ronnen us cns ,an aseo,a.. s.nuc oenec ec sm moam coemna,rc rseees anonzaars eces maen sae neu.c.,e cca aocnc arces neuraeer, coesero, auseoeen aow, a ereo.n some exam eco -, or an comnaon amoosa es, s ma comrse snec coesero, mresoxroamcneo, anne, ca-on-cw,-m-enooxeoox-e-,eneco caramo-,- exames, s ma comrse snec coesero,me,-amsenaororo-sann-e.cne sroome osocone, -c , an ,-noeox---meamn -- n o. oroane anor coneer c noomn-onmenns o, exeem coamrosonssesacr caeneer uesen caoneev aenr seuconuceoe escrenorrsse e a.,aureoecnoo s as a.,aureeers ,o.,o.,uus ,mmerman e n.nves.:,-o.,a anemees ee ar., e aa.u,reancoeecnoo,:oum-euume,er. eeruearr ,.-. s, sues arces ma aso comrse one or more oeres o s, e.., caonc ,cn- as am-no,,--n aone co--msesearomnoeos-a,- cooxnoea,n ceoesn-- - .n one emomen,eever vece ca ero, an ose seorn,or ne orncue ao, suc as an o vece cane orncu eexa amn ame,no..u, su.co a.s an oos.n one emomen,eever new.em.n.. ,, –.n one emoe smeenor,en,eorv eexram veec,ea caanraman,ncue a enveoe, suc as an oose seor e or oec.:-. n,or exame,orman e a., .a.^ - - oex oexes mnes a onoen emex ooes nemaenv,ee caerever ce ve mecmesr comrseoexes anoroexes. xames ooexes mae co ane annuce enocossnoe ces. xames ooexes an mexes comrsn s an non- comonens. conann s oexesncueu - reaen, a non-osoma souon a2+an oer comonens, zweronc amnos s,ae..,ormn ee mncrocomexes,oeenmne e..,rance , ano-sne . s are sne or oranen e emeoesmees an,aceaeev ceeru vaer ucesa ceom or vsaer coeus meneranees s. nanoszearceso sma cemca mo oecuar caroe..,rom comrseeren szes, amn ecues anareramens o . s marans o ac seuences, an cares.n some exames, s can cooacsame or aen oarsmanae mee.mrasn mea aneancroaueceeneo cveer o varous moecuar caroesoe enerraansonorn se memrane s vaeren mecansms, e..,rec o a , enocoss-meae enr, anransocaonroueormaon aunance osru os mcaure. vea cvear ane a ammnnoo a accs co sumcos aona eer conans a reave conan an aernanae ssne or arnne oras seuencesa acs.e rn ooarcare amno acs an non-oar,rooc amno r casss oewos aeres oe srucroureso arec reeerrees,o co ansaonnca oonnc n oorn a-mac, resecve. care oraverooc amno acrousa oar resues, wow ne o sserans-acvanra are crucaor ceuar uae.noere rus -.xam nscrona acvaoraromumanmmunoecenc x reerso aes o sncueoeneran,a-,ransoran, an-- escren.mnoexano.xames o s an reae acaons asoncueose or eac caros. a cnaanen cee useo. eo,rsn, us vuaro. an ex vvo worue rea, an exensve omzaon aacerec.e.,u reure.n some exames,s mae covaen conesescreerencno annazeeveoreeoo censu.ceno soemsee e.xa.,maesms,e, m-uncon aanzeor^ - - wonuceeoe-su ennccoonnazee onoe onruc meore acvanroens maeeveren comnaon exames,e-unconazeonouceeos eensco encnone oene on oer o mr moroer cones.n some maeeveren comnaon we-unc e acvanroens -unconazeo onaze cones.n some exames,e searaerome-nuceoes encone one or more acvanroens maeevere ano unconaze cones. reerso a sn oc enreeew - ems eo srumceunre,eever veces comrse nanocews. nanocew e snesze ron crce o amcae.o.n, w w a saanero om ac saeu oencaersn.ae a naenoncewe ma assem oe srucure.e sere maeneoae w a se- nanocewsescrenun e a,memo aoa.n exame o e a,newemn n. c :c.-.c nano:cew m-a aneun e.., coae w onu coae, oa ce enosoma escae. us ornno co ona oer emce aos ome.n,oee naver veces comrseo nanoarcesaso reerreo onuceoes encone one or monroe aacrvcaesn maroenosrm an coomr ceox w caros, e..,e esrcureeren.o nanoarces nes oe comosons s mae coae, e.., coaen a scae an an enosoma ercvaeoucmeecr,cs ™. cxoanmsruecs os, ano noanoarcesncueuraenseeraeucs' ano:–ee, e a..aomense:escr–e.nou, e a.. o sma monec ounees emrvoesmeen,ee evceren venrcaecs comrse . reerso a comnaon o anransuc euarever o naveroens,neenen roaneeane, uosnneae.-meae maeer uossemoaornouceeerra wnsuc aorn osmocoss an roaneeaneorer macronococ uaeno ces o exraceaunsaru mcaocrnom coomecouuens.^ - - rxaasm,es o meos an reaensncueoseescren'soo,aero, o eme ar.-aseae :–. nanoarcens o.nne e omr neocmesen,eever veces ma comrseomer-asearcese.., memraneuson.e emoommere-na,seeaorcmeer-asearces ma mmc a vra mecansm o vrus macner anormransecon comexses m wa c voamrorusse comonensa mmcnuenza , m, s , m , s a cesa es o nucec acse..,asm anvoveseo e u vae enocossawa, arocess cemca swcarm reanoenrs oe ana arccce s cuormaarmen.eownae enosomes acs as a ncene coso,earce reeasesscaeoarooro cecu anar aacconaes memrane crossn. scaeecnoos sae an maxmze .scvenosome awa sransecon ecenc ass usn a naura uae caroxa.na oener eamncoemeon,eeenomnmee.r-nas seoarces ma comrse aae anncue,u are me exames,eomer-asearces m.xam neo memoeso o,evern, ee.. c,o , , escreerenncueoseescrenrommeorsons o,r a coomweornuensoo ooe comosons eranoces.o:. .... ,romer rransecon oecnoo,rouc overvew, ransecon -acoo : er exemar u asners' noana.,o:. ..... ,,,,,, , -mno,mercarces, are,e,scr,e,n,, s, an, , , , reo . rou sreen oceocvcer veces ma comrse sreosn . s aoxnroucen a reverse manner, wac wo arsows correaeneovresn mammaan ce memranes. ma ac o ces wou comromsn overa vae.rx oamroeesn ose.., uncoueoaseoescer ceoson^ - - e:r, e a..necmmun:– aev, e a..rocacac mu–uncen , e a..e:e . eonanveoe-eanoevce s. esv mear c voemcrsees c monaen csoemrassem muu,n acona co ernev,e aoe-e nanoevce maurer comrse ce-eneraneee.., s n a m se. eneranee maene se.e env ear ocaarnne.e ce uncona comonens, e.., one or more o:oeeeonee macoe me.o.,oen wcrea osnee v oar more crcuaonme,ansoraren o seccssues scuar e..,orreaer ceua ces, aona ce-eneranees n some exames,erever ma,e asoer ean-aamncee eanrosoma es-cae, an, nuceareveras. ceuar nuceus an moconra.n ceran wc maaree conuae - , wc ma exaamrees,a aer mae a-ee- -ncueoseescrenoure, cancer ces.xames o s a..ccemes:– e. a..onroeease:– aamura, e n -coaee meevseoror voeusc sesca marces coae a comrse-coae mesoorous scaarces. - memr maneeso soero.us se scacaar cocres ma comrse a mesoorous sca nanoarce core an aoan caaces.n one emoem mean,aovree a szaers,eonree crnaem surace area,eano caro e moeoroan erenes sr, an overaarce szes ma moeo maxmze c o caros.e coan oearce ma asoe caro reease.xamesar oooa-cnoa,enc mreeassoe corcuaonmes, anroverecsearen an , e a..omae rous scaarcesncueoseescrenu onoranc nanoarcreas:– uree, e a.. ano:–. nanoarcesenceuveer car ves onc naenso mua comrsenoranc nanoarces.xames onoranc .vruevev:e–s.,asre me.es.,o asoroeusscr seca nnanoaeasrc aensosarseoes...,^ - - asescerscree omnn esuouo an, ea a..ce: , anense sca nanoarces sas xos zman..aoecno:–. exraceuar veesecevse,r w vecc ces ma comrse exosomes.xosomesncue memraneoun suc asroens, caroraeasn,e usse, ano c nouncaenc a ancs,e anver varouses oomoecues, xames o exosomesncueo comexesereoe.., s. an :- -naouss seescrencroeer, e a.,nerne. eneer. un :-, eo a.,arooc. ec :-no, e a.,um n some exames,e exuoso, e a.,umeneer. r :-.nreco one or more comonens omee c marao.onrm cer aa cno emxamexees., a., moecunnrec or maeuse wrs aaerroen an a como e o an exosome aaerroen.ers an nen oe caro maeuse w a secon assocane caro we exeo sseocmoen. axaameresr ooe sunc m eaxo ssoemcescancn eac oer,us e, e a., ueoseescren rv e a.eorm , naoe anr-mc. oecnn,o exemr :a.ro e:xos.omes-ncnum aeo aunss o. eos ae. seaorurenrovoacrez- :–sse anaren e a.ucecc os e- sesearc, ,o.,o. e. assemnnm na onnoen a erma cono emaernc,eseever veces a se-assemn nanoarce.e se- cane ae.es-a csasnem conann o nnaneo orar mocreeso aremenros.e se-assemn nanoarces assemn nanoarcesncue wnne ar.xames o se- uceccse ,u are nomeo,oseescrenceers e a., , no. avsearc, ,o.,o.,are e a. ,eemer, ,vo. ruercas e a.,aure,o, r . “uercarnr e oneero emro enoen s” ams reen a, caesse ov eenrn veeerece o cra nnae a suercareroen.s useeren osve or neave neeoreca care.on-muran, o ecxceumrrnarr soueenrcs ware unursoueans^ - - can,e an oose seornawrence e a., ,ourna oem c– ercanemcaoce suce . eren, a nucnc e once a es cmsem aossemes men,se a seruvcerure vermcaer can asese am nuceecro amc an ass cem.sescre ac moecues werene assemes are sr omose o nucec rzaon.e nucec ac moecu ucure aneoeer nucec ac meo, , , mxure es cane anorm o nucec ac,ncunu no assemes maeesne s o an , anee nucec acs.ucec ac meo,wo-mensona an crasracanee anrr aans n ourmerre oe-emoemnesronca saoesnecruon,u no emomen,e nucec ac assem ma comrse ora ns.n one “ oram”escres nucec ac asse m.s useeren,eerm onuceoe.e., a scao s mes comrsn aon sne-srane usn nume ranoeno aesre sae or srucure aneoeer srucuresnrocuus seorre sen-me senrasnonsa o s noucec aucress,.e., sae srans.xemar oram suraces arecaoons an n wc eac ses aa surace.ea ona nuceoes areone aer ees aneoeer sae srans. overans.ese sae ca onverea anse canoeeun’c orona’ ezne o we s seacec s nuracnesoenerae sae rzeo aare nucec ac ororm a comex c ac seuenceso overan ma rze w one w aesre caro.or exame, a sae o ee m moecuesno ce osr. moare oe oveer mans m maoeceue osuwesacrreacenre,n suocre as,veror oxvaemrane,s w maen ausnoceonnawzaer wac an, suc a asamoerr exoarmare,e wnoe receor.ae oe m moecuesescreeren suca enrze w one or more e m moecues.xam e nucec ac assem encoses an ses .oaer es o nucec ac assemes areescrenamo e a., ,:..s,-:. -acsanma.ce e arsons e a.,aommun, . s -- an e a.,uceccs a.,esaearcev,aer,,o- ,: . narx as we asnn .,o.,: . ernaonaucaonos. an^ - - noenouusareoroceeemnoemneserveeversems enec ee conanomescaeenesromneran vruses an moe erormmeernens.omooe ocaesuencoomness.caseescerneseavneeeeen r eeo ao.e,cen mammaan ceso :- an.:. scen,c we.ac are,n acso wreora asenn reernaonace.ucaonusos. een erence, suc ssemsave emo enmennee,reeoeuvnecron s assemevse arn s ensoemesnoours a re wroeee rmane o caro.ccornn one enoenous reroeemenerveeve enerveever ssem.n caae o se-assemn r ssemca comrses a reroeemenoee assoc o aeverarce an one or moreacan eemensa cane evae we carooeacae an wcrec encasuaon oe caronoe ereeor, suacrc ae.e enoenous reroeemen ssem mae a rerovraaroen oromoo , s, orrc,srv,.n, , , , , , , anor’ erverom an m one emomen,eacan eemens mae a’ uxraceuaronracenecon enscoen a reroeemenoee. necon snse omne eemo.menon,raceeevnerms ec voee nc ses memas comrs aere an a ex craceuar conrace macromoecuar comexes use enosmocac ass o srne-e euarocos cesrvn a seroue ceueraonecroenaoasno ,- , :. s -- -ar. memeseran mea.creerez e a.,aure conan a rue srucureousen a conr omoecuar comexes a seroen.aoaroe ace sea ancoreo aaseae an sarene e se, wc uo nsoaenoeumen oennerueorm assocaons w conracon.s cannaree an cceor reecooneon,acseorrace memrourane oer ceeuar maemora mnee va sea canoacera, or canerouce asree es.aceraa mranen sowno ex a vare ounconsncunos c oas usen esaveeennucon o meamoross, anos oseeon mouaon, ceavae, cassee erveromeoxc.n exemar eseooraus vruence rez e a..e. asmo encoamoaoocuesn cocnaacnserum core sorourcuarau asn as acmcessoorca.eneees^ - - n areecessearaooraee ansseesm o an aunnc, aosn wae e as a seenroee asvc-.ownsream oeseenes es mae enneereo aereaosa o anua rve reuaorenes.owars aesre ce e.saseenem erorammeo mouaerosm roens.e., ann cona onsrae usn s,e enoenousaoaoaneaoaroens n sorere-ermna reonsa arenvoven omans” cane noeue srucure oe e.ese-ermna “acan e useo noveaoaroens no nauraoae ono es.us,n one amcvoanmenr,oeense anveorr c veocnees masu csoemros aen an- eenrmnneere e werene one or more onuceoes enconeusonro aacanoman or one or more mouae enneernevcaenerereo.rosm oromn oe e mae reconon.e-ermnus oe roen, wcsnvoven euaroc ce ouarnnomana vcaerroen comrses aeca srucure w a a s cane rerorammeneoraacrse wum eauna creosc c ree raeccenorse.-reermz ena a.nemnonsormaae w eerermercuman aenovrusnooman -no or eerma n receor -seccesne anrn reearoen n -rown.aceoer erezu er ae.r comr.sncco ornen or m,onre onae emerormoeenn,s eneneeevreer vece mae an enneere e comosons anever vecesescreeono a ce oneres. arces, ec. maeever ren.e., vecors, vra vecors, escre erou a numer o mecansms suc as,or exame,ose acrsocaeow necon.-raevereos croonnecon oe c an or aou .n one emoarmoen,re mccroon ceecson ca mna aceeveerorme e ucsennc a, m e.c.r,o ascoovee rec a neeo aeare.e., s we w.–n.e cme.ncarmoeneercoon mearce ae c uese moemrrane anevere caro asms or ms encone one or more a n vro an ex vvoever. mae mcronece.n some case cvanroens anor cones, ce nuceus, anorever ms, me.cr.,onn vecroonra mnascree useo ao ce neucveerus or corecasm.on a^ - - c eenrcoann exame aces,v macnronroecenosn a mnaore c useoeverasmsrecoe nuceus or m ecroor onesoe coasm. eecroorana on o.noen ec emroomen,e caros anorever veces maeevere nanomeer-szeores woranon mea ce usuearu mseemran-evo oa ce eecrca currensoransen oen comonens w ronamcame es susenenuer, aownor cases, ers oens o nanomeersoownoe ce.n some ecro eeocraroonor maaone m uaseeo ursen v onro va arnous cees an ecenranser carono ces. ces aecnro soercaocn v moaa aes aone r uease e enox vevoveerveer ca.roonoe nuce o mammaan oseescre s, e.., nuceoecon.uc aroacesncue :–nuo, e a,.eerso.ne.es:.–e, e a..rocacac .rocacac: –.ecrooraaono mmamu an: an,uae.n vvo, e.., w meosescrenu soe useoevere caro c ronamc cermann, e a..aommun:. ever.n somreo exne aammvecr es,everro mnaam acsoeeve urse maoreeevreorrnmee caros, e..,orn vvo voume– o we souon conanneene en ca ra usn aare a suece.., an anma oruman, e. ronoeoosream o eareous .,or mce, vaea ven.soosncomresse, enancesermea ouno ma en roesuean a annnacrreenacsemna ceros, anamowcressureaemorar caae o crossn a ceuar memra nor caro no norma evern nae asm neoassno ces.s aroac mae useor enrc s, m moecues, anroens.eevere caros mae raensnecvoer,ne,un, musce, anorear. ransecon men e caorsos,o er.n.,roeuconn nuucceeoc aecssescnroe cese.ren, maenrouceo cesncue cacumosae-meaeransecon, caoncranxsameceosn, oroasnosmeecoranns meecoons,^ - - oencramrearnsreacnsoenc,orno,reea socransecon, maneoecon,oecon,maeecon, eoscs ar aen-enance uae o nucec ac. nrouceo cee csar usons, a e..o,sec moenouc oeroecesn aune.ore cerom ones aescreeren, cane reersoeever o nucec acs r “osc”, as useeren emomen,e caros cane aace, aoss coecase w, o-sr oeeerwasrec coeuoemoaramrecne.n one an caneevereoe ce va aeneunsee e..,a s, wc vasev e a..a.omm.: rea-sn e a..a.rooco.:- .n one emomen,earces c caane e a., .an..:-rumarces aneo,unsen,aaum, roum,anum, or mana ncororaesn o oe. rneev s c eomces aeo wmen,ee comever ssem canncue anmanaeevcea eren.arousmanaeevces areeosscroens onr ceom ar,o annensnc ouee an comeosonsescre comosona canemaneno a suec vce,ra, or oer . . eosno ornen emuconmene,roenorerenaon roenorerenaonno mauereres ceens, wscocsu croemrorvsesesnroor mucenosornucn ce or more oe comosons oronuc no aaressue one comrse eoesescreeren.n one emomen,e meos onuceoeveesr enncoo anar onee orss mueor we aere ceroenorerenaon occurs, one or more roenors.n one emomen,e mecovsa conmrroseenesvearnnouc aeareerenssuaeo onne o ce comosons comrsn one or moreonuceoe or more anuceerenao s encon one or more acvanroens maeormuaen onne o or m coereeroveenro vres.cne osn aes emomen,e one or more comosons e one or moreonuceoesoearessue.esncr onee eemreon amnen co,neur oeneo ore mvoerer^ - - enoonueceao ceess mnaeearoremusasuee w sucerenae aec onvea onr mororeenos anreucesoes areevereo e enoea ces.n one emomen,e one or more a ae on a surace o o ceroenorsooueosve ces.n scvanroensnuceerenaon roens comrse an aons o ome exames,e one or more acvan awa, oro.n some exam aesoc snanawa or a ce receor snan ae,ae, or a comnao,e one or more acvanroens comrse , , exramc nereo.n one emomen,earessue cane an n ossue. or more connees e omroonmuecne,oee mse encoosnescre oene oerr menor mea courneesr. conm orseevern one one or more cones mae seeceonuceurerere ne emomen,e asrom ceso sneosve ces.n one emonaon o ceroenors suc rom-, , an,-,-,-, or a comnaomnen,e cones are cosen e one or more cones comrse-, , or a c ereo.n one emomen, e one or more cones mae co-e omnaonereo.n one emomen, one or more acvanr vere we one or moreonuceoes encone n one emomen,e coeonsn oesr meavereee sevearreae usnrom ane o onee ore movreer ac ssvaemnsrsoceosnes. oenree onr. moreen ceovnerees mna a seeaeraveereevreror voe, cconecurorrmee one or more acvanroens,e e one or more acvanroens.n one n w, or suseuenoever o cones oronuceoes e emomen, searaeever oe one or more ever oe one or morencone conesaesaceemora w resecoe s useeren,oeenrumc “eoemeosr eancone acvanroens. reersoe amnsraon ore ” or “emora” w reseco coneever a secconnmeaveerr o cones oronuceoes encone cones a onuceoes encone one orsromeonnmeurn wce one or more n one emomen,e more acvanroens are amnsere orevere. cones areevere a one or more cones oronuceoes encone one or more acvan aonnme aereever oeonuceoes encone encone cones arroeenes.venre one a e amoonmnen,mee oenoer oer meoree cveorn oes oeroonnuucceeooeess^ - - e onrc moorne coe onnees o orr moore ancucveaonesr eonceons.nn onee c emoonmen,e searaeever oe one eever oe one or moreonuceoes e esaesace saa w reseco s useeren,eerm “saa” orn “csoana” we ac rvanroens. oe amnsraon orever o cones oro eseco coneever reers ssue, or oranaersrome c nuceoes encone coneso a ce, encone one e,ssue, or orano wce one or moreonuceoes or exa omr moer,e a acvanroens are amnsere orevere. roens areevereoeervee orn,e oer m onoere oro monruec ceooense esnc oornonuec oenoe ore mso erne acvan cones maeeverenravenousnoeoo crcuaon or maecone erenssue suc as,or exame,e seen, smanesne evereo a enconen a ocnev eamnormoeenn,s o cnae oar meo ore ancuvcanneroeen, re c e nocm. aoosn oons oronuceoes, scoseeren, maeevereo aare ceouaon ex ceroenors asransanaon oeransuceare ceouaon vvoransuconrororansuceare ceouaon mae cuu noe suec.n one emomen,eransanao ren vro, an oona ce sore,roro nn onoe suec. exame,romn ae emoso,m anen,ee cearse cu ceureonua voron mraoreo esxoa vevorroamnsuec soun.ecn, oor emomen,eare ceouaon ma comrse sem ces resennear ne emomen,eare ceouaon ma comrsever sem c essue.n one emomen,eare ceouaon ma co es, e.., ova sem ces.n one moceroenor ces.n one emomemrseemaooec sem ces s or moces ormoceroenors.n on n,eare ceouaon ma comrse ceroenor cessoaer e emomen,eare ceouaon ma comrse ouaon ma om a suec'sone marrow.n one emomen,eare ce sa, ae comrsenuceuroen sem ces s, emronc sem ces s or erenaon aorn ex vevo ceransneuaceonr,o arreo cruanusreanano vnrono uneer su coencsoenes,ora enuce ras-ena e a. uman sem ce-ervemc eea ces enance xame, eveomenn a xenoenecmus.er nmmuno. a :um-an-c.en^ - - one em anomen, aenraonrsuce,are ce- ceosuaseeo,n mora exaem cee,-sorennoor see ec aor , aemooecroenor ce erenaon:ow comerc assessm . mus.raemao. :-.n one emomen, ennone marrow an comrseeoroc muoen sem cessse eare ceouaon ma enneen ane nces o eea sem ce,or exame,aazzn e a. oencneumanmus.eve. :-es w.e.n oeoroc muneae ceouaon maesoaerom amus orano ne emomen,eare aen caono. ,e conen o wcsese,or exame,euse.. s enre. ncororae reerenceerennno aaren ossnuee e,moro exammene,,ernanescuocne, e.ar.,en coeeo suueaco'sn mvear,emraunss, aannerec n anoer emomen,eransuceare ceouaon m or seen. marrow ceroenors ormoces a comrseransuceonenecon.eransuceone marrow cear coaneneo arsm manseerne moraee sou anec coonnzrea aveanous ssue, e..,e suec'sver,mus, an or seen.or e re ensuresmocesavn a an or sxame, coonzaon oemus socoma anens unero neavee-ees ore suec's maor roenors ormoc seecon, wereasoseone marrow ce osve seece.n oense eamvno am weena, aenransourceo cneas msar ororw cass ce moroecueneso mae comrsear moroenors s.n one emomen,e s ma crs ma , -, cessee,or exame,cwarz e a..eecvemuomrse reuae cone an cemone receors.eourna omm s sen n one emomen,eransuceone marrow cer unoo, ,- . receor or see,or exame,a oenors ma exress ernemoran roenemo seen o murne auro e am.us.e an a an . uoco. :- s encon onne eme oonem oern m,oree o ancev oar mnoreroonuceoes comrse one or moreasm onuceoes comrse one or more ms enceonsn.ne on oene e omr moormee anc,vaen onero oern ms.orne^ - - one ems aonm men,es. onne o orn meo ermeoonmuecne,oees o cnoem orrs meo a comnaon o one or moreasm mocaonsancrease m sa, reu re ms comrse one or more ecenc.n one emom cemmunoenc, anormroveransaon e one or moreonuceoene,s aree meverse co vma arse se n-arneoacracne, m an exos.omne o,n ae emomen, a vra vecor, an enneere reroeemen vec mcrovesce, exraceuar co or, aonuceoe-ase nanosrucure, or an eosornraecenecon ssem or asescre esewereeren. roens, or coemrnesn aenn ons osc aocsaun vrae aa nseoc roroevva nsens a mroeeonsorenn canae acvann aaressue.n one emom ,anuce ceroeraon anerenaon onuceoes enco en,e meo comrsesaevern one or more erenaon o cn one or more canae acvanroensanuce ce seecn a samee or sonene coro cnee cseos a exoreussanon oe c caensaerev aecvraomn arsosueen oneres, ouaon o ceserveromessue oneres,crean aou srome we same o sne cone ces exressne can aon o ceroenors eercenae o ceserenaeromeou ae acvanroens,uann eonuceoes encone canae aon o ceroenors, ane seecn or evauaonn vvo, w acvanroensa resuen ceerenaonoa ceouaonereneercenae oerenae cess a or aove oe emomen,e conssn oeerenae ces an ceroenors.n one co ssue oneres caneever, seen, smanesne,mus, or a omwnaonereo.n one emomen,e same o sne cone ces cane seece usn . comer. eecve amouson, aenscroreeaeren arearmaceucaormuaonsa can conan an amoun, mor s eecve amoun, anoreraeuca eecve amoun o one or ereeo comwocun asre, m aosoec reueersr,e como aosseonsr,m vecors, vecor ssems, ces, or a comnaon escrenreaerea esewereeren aaarrma acceuveca aen ac ocrenaree ceanrre ers oerw execreener.ens^ - - u osrenreerenen, “ warm aaceuarcmaacoeurmcuaaon ac”c reeearseo caerr ceorm orn eaxcon oen a,n m acve aen, comoun, suaeoranosc,eraeuc, orrevenve usen vro,n vv ane comoson “armaceuca acceae carrer or excen” r o, or ex vvo.s useeren, rearn aarmaceucaormuaona eerso a carrer or excenas useun or oerwse unesrae, anncu senera sae, non-oxc, ans neerooca as we asumanarma es a carrer or excenas acceaeor veernar usene secc ceuca use. “armaceuca acceae carrer or excen” as use enr aon an camsncueso one an morean one suc carrer or excen. armaesen,e comoun can oonaeresennearmaceucaormuaon as a suc asc aenu accave anccereaene, s aan. on onee e cmomoosmeonns, ore comarmoanceenuscaereoormueascrone cannncue, ea esewe reaer sa oe acn ore vneee n ermen reo. enm.ens, usee acerveen,n “rearemnacesurceasen a acs aarmaceuca acceae orase aon sa wose couner-ons are non-ox ceae sa” reerso an acnarmaceucaoses oe sas.uae sasnccuoe sueco wce are amnsere osae,sonconae,acae, sacae, ac e,rorome,oe, nrae,suae, arrae, ascorae, succna crae,arrae, oeae,annae,anoenae, ormae,enzoae,uamea, me,ae maee,aennesusnoanea,e,um earaaen,esuucoonnaaee,,uecnazreonneaseu, soanccarae,ouenesuonae, camorsuonae, naaenesuonae,roonae, m ae,- maae,aae, ana aonae, maneae, neeereo vea anarm suacem auoa ecae. meoromu oar roounseeoscreeren cane amnsereo a suecn roues canncue,u are nomeo aur a suecn neeereo.uae amnsraon eecro-osmoss, en cuaroc,ucca, conuncva, cuaneous,ena, ex ocervca, enosnusa, enoracea, enera, eura, exra-amnoc, arerracao,ronreraa-a,rceumaor,anrsas,anr,ranroan,ronnceras,an,ranurras-aa,nomrancaar,nra-amnoc,nra-nracaua,nracavernous,nracavar,nrac ac,nracaranous, ena,nracoronar, erera,nracserna,nracornea,nracoronanrauoena,nraura,nnrraaecoreorrmusa, cnavrearensoosuma,ean,rnarearmasar,c,nnrraasnca,va,nnrarauceaa,,^ - -nnrraaoecsuoanra,,nnrraaouvmarnana,,nnrraaemrcaarca,,nrnamraeeuroanre,a,nranmraenenuea,nramuscuar,nraumonar,nrasna,nrasna,nrasnova,nraen ra,nrarosac,nraoracc,nrauuar,nraumor,nra nous,nraescuar,nraeca,nravenousous,nr manc,nrauerne,nravascuar,nravenous,rra avenousr,nravenrcuar,nravesca,nravrea,onooress, oroaornn,eaar,n oeear,, naaresan,era na,soeracsuracn,eo oucsc,uesrvaercureasrs,nereucran,ueer,ne oamc, ora, reca, resraornaaon, rerouar, sossue, suarac ura,eroona, sucuaneous, sunua, sumucosa,oca,ranser no, suconuncva,ransracea,ransmanc, ureera, ma,ransmucosa,ransacena, comnaon oe aove amnsraon urera, anor vana amnsraon, anor anreae anor roues, wc caeens oneseaseoe eree a acvreonreens. ces rae, comouns, moecues, comosons, vecors, vecor ssems, sue,c orn a n ceoemneareoon ase arneonreescerne, sucn arsea aner acevaen esreeweenre ore areenn c,ann aearromvaceeo a ormuaon.s suc, asoescre arearmaceucaormuaons conann uca e comouns an sasereo, orarmaceuca acceae saser one or more o uae sasncue,rorome,oe, nrae,suae,osae,esooescreeren. sacae, ac crae,arrae, oeae,annae,anoenae, nconae,acae, maeae,ensnae,umarae,uconae,u arrae, ascorae, succnae, meanesuonae, ea caronae, saccarae,ormae,enzoae,uamae, naaenesu nesuonae,enzenesuonae,-ouenesuonae, camorsuonae, n oonnae,roonae, maonae, maneae, maae,aae, anamoae. emaooecseea esme oomen,e suecn neeereoas ors susece oavn a esewereeren, r a smomereo.xemarseases areescrenreaereao an su suc asn connecon weraeuc meos.s useeren, “aen” reers cannsance, comoun, moecue, anee, wc caneooca acve or oerwse useeurecen a, “aocovec aae ann” oorr “acsvoeoncrae eene”c r oene ars suo aec suos wancec, coms aoumnn,s orer meoeoc.us w wccsoso acman ascervee oor. one orwesre, wnorusc e,o ,es “a acvoeo aecna” or or “ascovoencare eeenc” on re ae srusoec a^ - - c coommoonsenon ors co amrouneen.s on a a ceonm coasnoen ao wrmcar aec wveo aee onr,a orr on oe eec oe comonens o a comosono wce woe orar oe eec o er wors,e arue.n aen cane a seconar aen, orn oer wo e comosons comosono wc an aonaar anor oer eec rs,e comonens o a armaceucacceaearrers anecona oe comosons arue. earmaceucaormuaon canncuer anarremaecns anens uaearmaceuca acceae carrers euca acceae carrer. acoos,um arac, v ncue,u are nomeo waer, sa souons, suc as eeae os,enz acoos,oeenecos,ean, caroraes o,aac aocse, a emseross,e or sraorxc, m meanesceumu soseea,ra aen,aco, svcc ac, vscousaran,erume eeerous r n rroone, wco no eeaca wrme acve comoson. su aceucaormuaons cane serze, anesre, mxe w aens, oscmo ascuresrscuarne,s,ureesres,rv caoovresn,, saavozrenrs, wen aens, emusers, sasornuencn noeeerous reac we a anor aromac susances, anee wco amoun o snec oonnea erm aocvmee an,cv ensee co ,ncamrumoau ncneu. uca noormuaon can asoncue an eecvencun,u nomeo, e..,onuceo meo,ooc aens or moecues aamers, rozmes,or es, amno acs,ees,oees, anoes, a mones,mmunomouaors, anrecs, anxocs, anscocs, cnaemeoscesr,aeu acns,smaasmnoncs a,ens a,n se-nsnazmerms,a anore cso, an-samnes, an-necves, ecve mnaonsereo. aen canen a om nn eeo eu emns cvoe ammeonu,ne amoun oermar acve aen anor oona seconar s useeren, “eecve amoun,”e raese erseocvee a ammoouunn, o aneorrmeraare auncaor o eoencave amoun. aenncuenearmaceucaormuaona aceve one o seconar esre eec.s useeren, “eas eecv r moreeraeuc eecs or anor oona seconar aena acevese” aem oonuen or re meorrseoeraeeouwecs o arm oouenr oesree ermecars.^ - - os uosnea seecren, “eraeuca eecve amoun” reersoe amoun oermar anor eraeuc eonecars. an oennencuenearmaceucaormuaona aceves one or more acn vro, ex vvo,n s eum, oronm ven,e one or moreeraeuc eecs areo mo a nucec oermare a enec oveo amoun,eavso. eecve amoun, anoreraeuca eecve amoun armaceucaormuanoan c saenconar acve aenescre esewereeren conanene ,,,,,, ran,er,om aouo,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,,,,,,,,,,,, n,,,, m,, or, or,, numerca vaue eecve amoune w e an n on em a canonm o een an,ese ee r ean ecee vcs. eve co anmcoeunnra,eoans, eeaescv ee aemcovuen, c aonncoreraeuca eraeuca eecve concenr enraon, anor ,, aon, wc can eac ranerom aouo,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,,,,, ,,,,,,, ,,,, ,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, n,, m, or ore an numerca vaue w a ,, or , n oer emomens,e eecven oese ranes. eraeuc amoun,eas eecve amoun, anor rom aouao ee,cv,e am,ou,n o,,er,ma,r a,n oona seconar acve aen can rane ,,,,,, ,,,,,,,,, ,, ,,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,,, o,re a,n nu, ,,,,,, ,,,,, mer,ca v,aue w, a,n o,es,e ran,es.,,,^ - - earmacneu oncea emormoumaeonn, cane rarnmearro amnore oona seconar acve aenresenn .,.,.,.,.,.,.,. a,o.u,o..,.,.,.,.,.,., .,.,.,.,.,.,.,.,.,.,.,.,,..,.,.,.,.,., .,.,.,.,.,.,.,.,.,.,.,.,.,,.,.,.,.,., .,.,.,.,.,.,.,.,.,.,.,.,.,..,.,.,.,., .,.,.,.,.,.,.,.,.,.,.,.,.,.,,.,.,.,., .,.,.,.,.,.,.,.,.,.,.,.,.,o,.,,,.,.,., ,,,,,,,,,,,, ,,,,,, ,,,,, ,,,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,,,,,,,,,.,.,.,,.,,.,,,.,,.,,,.,,, ww, vv, or wv oearmac ,. n one emo eucaormuaon. ormuaone.., as armamren an, wore orre se aco cnear aocuvae aonens,rees eenenearmaceuca ranerom aou cesox1m,20cve am1oun o ce2s can x3m,x4m,5x6m or7more, suc a8s aoux9m,x10m, x11m,12x13m,x14m,x15m,x16m,x17m,x18m, x19m,oxor amou,xx20mm.,xm,xm,xm,xm,xm, arcesenn onee emveroemee.n.,, a veru amsoaurnc oer eavecnve amoun,arcuar were annecve e eecve amoun o vrusarces cane exresse aes armearr oar sueecoonrmarn a uenns ase ar caro, voume or as a muc onecon.n one emomen,e ee un o x1arceser, n,, m, orox20arces cve amoun cane suc1a2s aou13x11,4x2,15x3,16x4,17x5,18x6,xe7r,x, n8,,x, m9,,x or10, orx mor1e1,, nx,,, mx, or,.xn on,ex emo,mxen,,xe ee,cxvee,r cxan19e, aooour axou1xran2s0arceser, , n,, m, orox20ransormn unser, n, ormn unser xx11,4,xx21,5,xx3,16,xx4,17x,x5,1x8,x6,1x9,o7,orx ao8u,xx9,2, 0 mx, o ran1s0r, or m ormxn11ore, suc u,nxs1e2as ao r,x, n1u3,,^ - - ao,u m., oro. onr o mnoer eem, suocm asen.,,e.,., o.,earmaceucaormuaon can ranerom .,.,.,.,,.,.,.,. .,.,.,.,.,,.,.,.,.,., .,,.,.,., ,.,.,.,.,.,,.,.,.,.,.,.,.,., .,.,.,.,.,.,..,,..,,,..,,..,,..,,,..,,..,,..,,..,,..,,..,,,.,.,.,..,,.,., .,.,.,.,,.,.,.,.,.,.,.,.,., or m ,.,.,., aensesncr onee emereonm coenn,anee amnoune ora erecve amoun ooree. one or more oe acve o aou m ase uo maceucaormuaon can ranerom aou owee oe secca neowe oe suecn neeereo or averae amnser enouaono wcearmaceucaormuaon cane ormuaon,n. eme eoecmevnes am woeurne oerees se ac soencoanar aen conanenearmaceuca seconar aen,ermar aen,e amnsraorn r aocuev,e su aeenc a we, vaserase,e seane on osnease amon oerns, w canencueneac w armreascee en on e, en oon ucne o ae or orman urmar aaoc senu orcan canoer em ar xu. saon,e seconar acve aen armaceucaormuaona c as a san-aone comoun or comoun,ervaveereo, oranarmea acemuncaseroerm cuonaeomnorearneeoous or seuena we aouo,n o,ne, em,,o,m,en,,,e e,ec,ve, am,oun, o,e, seco,na,r. a,cv,e a,en can ranerom ,,,,,,,,,,,,, ,,,,, ,,,,, ,,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, .,.,.,.,.,. ww, vv, or wv oeo,a s,,,,.,.,., armaceucaormuaon.n aona econar acve aenne acve aen c emomens,e eecve amoun oe seconar ,,,a,n ra,nerom aouo,,,,,,,,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,^ - - ,arma,ce.,.,.,.,.,.,.,.,. ww, vv, or wv oeoa osauecaormuaon. n aosaeno o or rmnmes . emeoosmaene,orearmaceucaormuaonsescreeren canerove orm cane eec m cane amnsereo a suecn neeereo.eosae sene suecvne neeeneraeer seoec.cs c uosnecenerraeno,n “, sousce, as an eecve concenraon, a aven scascree uns suaeo ” “unose,” or “osae” can reero oermar ac r usen a suec, eac un conann areeermneuan armaceucaormvuea aonen,er aeno c oacuonaaeoresreonuc seeconeaersre ac rveesonnsreen, anor a assocaon ws amnsraon.n one emomen e or resonsesn amnsraon se.n one emomen,even s ,even sesroxmaoe cases,eosaeorm conan essaoe amnsraon se.n somenea s areaer amoun o one or more oe acvenreensresen orocaornm waceuncaeo surmuecaoon accaonuneornaosnse onee a amcovuen c noemeoeo reac a secc reon seconass m nens suc as vars an rorae roeea ueoo ssasm nce. uorms cane aaeor amnsraon an arorae roue.nraocuar,nae,nrane,asau, aorec naonmcueno, ouracca,nc suunnuau,cc oar orarn ssuernua, reca, arenera, sucuaneous,nramuscuar,nra ma, vana, arorae roues aree venous,nernasa, annraerma. er meonow scre esewereeren.ucormuaons canereare an casues,eon esan s oee ro a arrm. ess, aaoweerso orr orraan auems,n ssraon canscreeosae uns suc as aueousus eeo ouons, or susensonsn aueous or non- emusons.n one emoammesn o,r wesa,r omracneu oc-an-woarmeruauons e amauseonso orr o wraaer-n-ou asoncue one or more aens wcavor,reserv amnsraon ormuaon.osaeormsr e, coor, oreserseearmaceuca souona caneeveree asa areoaomr, o srara a,m ornsurao sonu canon a.soee oranoesaoremo orm a canue^ - - a canmnes merceroeno a suecn neeereo.ere arorae,eosaeormsescreerennreen.neca oneossu eaa mee oo.rmmen c,an co amsoounes,re moareecueos, croomonos oron ssu,s vaecnorse, v reeceoasre o an ces, or a comnaonereoescreeren caneenre ssems, one emomen,ermar acve aense en wose reeaseseae.n emomen, an oona seco nreen wose reeaseseae.n one meosorea nar aen caneenreen wose reeaseseae.uae emenenrenenes rne meaaseer oa annonmreerse,n waxn,cuese,, anu aere neo.emaee reo,ea csoeano or ormuaons canereare asescren sanar reerence sae ormaes," es.erman e. a.ew s suc as "armaceucaosae scence anracce oarm or,arceeer,nc., , "emnon -e an "armaceucaosaeaocr", e., nco ams ns,amore,,, : ams an ns,m.s aneruever ssems", on,nse e a.,ea, eume se reerencesrovenormaon on excens, maeras,aes ann, aneesro,c ceassseuseos,r anrearrannueas.ese ane caaesu reese aneae reeaseosaeorms o ouro aou mo ase cane anwererom aou an xans or more. ome mes o suae coan maerasncue,u are nomeo, ceuose mers suc as ceuose aceae aae, roxro ceuose, roxro aceceuose,roxro meceuoseaae, an roxro meceuose meaaecr succc rnesanesoav arne com acmeearcea aavaaea, aecr uncer aceraoem nearms an coomers, an arma,esersa,erman, zen, seac, anosaccares. e onso oans maeorme w aeren rao o waer-soueomer, waer non-uoemeorcm eexrcs, aneno,roroeuecneeneeosrmeer rse,e wase orro we.oue waernsouewaer soue oneosaeormmarx or sme wcncues, coans eererorme w or wou coaeeas, casuesw orus nomeo,aescomresse comosons, "nreen ass"orm wou coaeeas,eas,arce osaeorm. uae as,u nomeo, susensonorm or as a srne^ - - emomens,errem aarr aocrvaee,nreeeonsase, aonrmosr oescornae seceornenar ca ancvee anreosoemne.nese armaceuca acceae saereo were arorae arencoror s, anor emomens wereeosaeorms aosome,earmaceaeno aosome.n osomaormuaon.eosomaormuaon cane am ucaormuaonsus a osaeorms aaeoroca amnsraonn csaereo a suecn neeereo. creams, susensons,oons,owers, s neormuae as onmens, emomenorrea ouons,ases,es, sras, aerosos, or os.n one earmaceucaomrmenusa oonse a eree a or oeer as ex aeornacas osunesm,eonr e oxra cmreame.e meonuor omruaee sn, an onmen, armar acvenreen, oona seconar acvenreen, an armaceuca acceae saereo were arorae caneormuae w aanor waer-msce onmenase.n oer emomens,ermar anor s ranc ornreen caneormuaen a cream w an o-n-waer cre econar acve osaeorms aaeoroca amnsraonne amase or a waer-n-oase. mou wase mouncueozenes,ases, an susensonros. osas,eorms aaeor nasa ornaaon amnsraonncue aerosos, souons, seco es, orrowers.n one emomen, armar acvenreen, oona enn aaros aaceveornmre aaene, anorornaaarmoanceusnca aa arcccee-aszee- sraeuceereoor wmerea arorae can oanae mcronzaon.n one emomen,earce sze oe szes oane or mcronze comoun or sa or sovaeereo,sene a vau reucee.., mcrons as measure an arorae meonownne a5r0e o aou.o aou amnsraonnaaon asoncuearceuss or mss..osaeorms aaeor e carrer or excens auor amnsraon as a uaeosaeorms weren o souonssusensons o an acv nasa sra orrosncue aueous or enerae varouses o meerermar anor seconarnreen, wc mae nasanaao eoseressurze aerosos, neuzers, ornsuaors.e nn onoerm eumaoonms ceann,e amnsereo a suecn neeereo. amnsraonnaaon. eosaeorms are aerosoormuaons suaeor souon orne susenson on a somrmea or aecseve emnoremeenn,s, secoen aearroso acovremunareone cno,n aannso ar^ - - auaremouasce our ncoan-a aucecoeusa soeve san.eerroesoo woremreu aaornosr caae an aarmaceuca acceae uanesn sereormn a seae conane neresenen sne or mu-ose conaners a sneose or mu- r.or some oese emomens,e seae e.n., e mxeaeurseeo ose nasa or an aerososensere w a meern vave ee senaer, wcsneneorsosa oncee conens oe conanerave conans a suae.reeroe aeeraonso unoesrareessourrme, ssuc con asa conmen an aerososenser,esenser roean,ncunu nomeo aro resse ar, caronoxe, or an orancn oer emomens ar uorocaron.e aerosoormuaonosaeorms aso conan a souon oer c ao snuasneensonn a ou amr-amoamrz aecr.veenrreessuernz,e o aeoronsao seormuaon cannreen, anorarmaceuca acceae saereo.nure conar acve ormuaon aso conans co-sovens anor r emomens,e aeroso sa anorase anornea moersncororaeomrove,or exame,e ormuaon.mnsraon rce mass caracerscsamoun anorroe oe or examorme, oe aerosoormuaon cane oncea or severamesa, aeroso ,, ormesa,n wc,, or moreoses areevere eacme.e oura soonmse canosae aemonsereo a suecn neeereo. armaceucaormuaon rms suae anor aaeornae amnsraon,e aen, oona seco s arowernaaeormuaon.n aono armar acve aro nar acvenreen, anorarmaceuca acceae saereo were mannroa, aen, suocr s aarcos.ane soomrme o can ceosen eamn aoomwenesr, aasrem suac asacose,ucose,reaose,nreen, anorarmaceuca acceae r acve aen, seconar acve reuceorm.nurer emom saereo were aroraesn aarce-sze amno ac, ceoose ocaaceae,en ans,o ar mereoarmsa snaces m oo seaerr,c s aucc, a ssuc-e ausc mnea onres anuomer cacum searae.n one emomen,e aerosoormuaons are ar or ose o aeroso conans areeermne amoun rane soa eac meere oe comosons, comoun o an acvenreen, suc ase one or more eren. s, vecors, moecues, ces, an comnaonsereoescre^ - -amons, creoamsas,eeosr,msas aeas,eoamos,r o vra snraa aormmnusaraonos.n coaneresene asessares, amnsraonncue suosores or enemas saeorms aaeor reca a suecn n .e vanaormuaons cane amnsereo oeseaeereo. ncue aueous anoormrs no an-aaueeouosr searreneenraec aomnn sosuraoonns, a wncor a cana ceoornecon can uers,acerosas, souesa renere comoson nan anoxans, an aueous an non-aueous sere suse soonc weoo oe suec, cenn aens.eosaeorm nsons, wc canncue susenn aens an sne-unose or s aaeorarenera amnsraon caneresenen a vas.eoses can mue-uonozese c aonna ren-seurss,ennceunn a suer noe camrreeroo re sceoanes aumeouees or roro amnsraon.xemoraneousnecon souons an suse ose one emomen,rom sereowers,ranues nsons canerearen amnsereo a suecn nee , anaes.eareneraormuaons cane acve aen,o sre scoomnea erm aocvmeennsr,ere eeo eno. ,sa aneoorrm caornmaacnes areeermne amoun o armar aroraeer unose.n an emomen,e uca acceae saereo were seconar acvenreen, a reeermne amoun ormar acve aen, e an eecv norarmaceuca acceae saereo were arorae can emomens,e aemoruene, aermeanse e aemcou anmo oun a, arnmaorr a acevrea aeuenc,a seco enecve amoun.n oer armaceuca acceae saereo were arora ar acve aen, anor eec e, cane an aroraeracon oe ov-e aemroun oe acvenreen. a comnana on onees re e a amn meoo nmm orenn co,ao men naare omra nacee euscaormuaonsescreeren canear o armaceucaormuaonesc ra.e comnaonreamen canncueereamen moa cane a creeren an an aonareamen moa.e aona mouaon, envronmena moeumaoone,ra aeuscc,a a acovoc maoueraaoenu, acn, su cromer,na raonasone,reoe. nomen oon,e eomnoucmeoen,es,e c aom-noera ac osr, comeneas,onoerae caens, a anoonaes,n acuameerus,^ - - r anoszamsmeso,cosr,m aonne-sn,mammmunaoomroes,u aano-rs,s anrecs, anxocs, anscocs, anaescs, aens, senszers amnes, an-necves, cemoeraeucs,man mnsrao, an comnaonsereo. ena oearmaceucaormuaons amnsere one orr mmoacreeumcaesoorumru,aaons, o mronosa,e ororemarseer.eo.,,es,cr,e,,e,ren cane m,o,me,n,,e,arm,ac,euc,a,orm,u oar monosre ormoe ,,,, e ssaoeurorm,sae,re moonescr, oereaer.n one amnsere connuous over aero ome rannrom mnu ren cane anosaesorms arenownne ar anescr esooursoas.evces connuous amnsraon oearmaceu eerena are eecveorove emomen,ers one or aewna caormuaonsescreeren.n one suseuenoses.ssca ree amouns amnsere cane aerosean manenanceose, resec rreone ar as aoanose oroses an a amnsere sucaevoeses. ovner oneme em areoameeren,necreasaerm oarceuecrceaaseorm ouvearomnes s cane wean a suecraua o o aarmaceucaormuaon orrauan o aso earmaceucao rouce a sueco amoun o asrmreavro aur csmua ve asoceun ns.s,e se,conearar amcacveeu acean,o arnmuoaronar cmanac ceouncaan a acrceeeaermen sae aerreoor waeerreac aorno oraee. enec somvee a omounese o emeo acmveenns,reeenre.euermne amoun cane an e amnsere once or morean once aa, mo c unoses maereore era, mon, orear.ucar n, oreare..,,,,,,, or moremes wenownn maceucaormuaons maereare an oe meos su eree a cro-.eraes or muearmaceucaormuaons areoeevereo a eueecn,ae amenresnraeornase as omrnorsmruaaonon ws cearne aen a amrencsaeree seuena or smuaneous. amnsraons, suc as morean aou, amoun ome occurseween amnsraonsn seuena amnsr ,,, mnues or more.emeeween ears,eenn one acve aenraeseonn cnan eace o anmen osrraero on.oumrus,aaneso,u ms aonmsn, osrra evoenn^ - - remeerse.o. a, wmnnsr saecoonn os owrous or a meowreormuaons ae sameme or susana ae same amnsereoe mnues aar, wereenensaeormuaonse . er ae sameme. e aove comsoosescornse aner meen aores conann an one or more oe eemensscosenauere s.n one emomen,e comrses a vecor ssem as one or moren oor onneuc oreo morees o encoe cnomoene onnse o or meo comoson asaueren, suc ase erenaon o ceroenor ces re acvanroensanuce ce saonu anor one or more cones oronuceoes encon cones, acneonsesr,u acnonosr aore uvsenr veece. conemuenres moaeveer sraonuceoes anor comnaons, an maeroven an suae con ovenvua orn one emomen,enc aner, suc as a va, aoe, or aue.n seccoe acaons anu mesensorusceosncrsne oneer oern m.onre onaen emuaoes.mensrucons mae or more reaensor usen aroces en, a comrses one eaens ma s uzn one or more oe eemensescreeren. a maroveer oonve oer mno aren re saucaone o cro snoaraneer, suc as a va, aoe, or aue.or exame, as usaen aarcuar as uers.eaens maeroven aorm comon sa, orn aorma reures aon o one or more oerncunensue noorem useee.o., an so counmcen carareon oareouer,ze a soormu.uer cane anuer, uer, arsuer, a uer, a uer,mcaronaeuer, aorae emomen,euers aane.n o an comnaonsereo.n one .n one emomen,e comrnsees em oneo orm meonr,e oeue veercoarss a anorro omne a ooru moreo aou onuceoesescreeren.e ma avanaeous aoworo oe ssems oer ve a eemens oe ureerse enmoscosure. usraveuroses on anmen arse n aroenuesnraeeonmeoe socwone oxaemsecso wsurec. arevenor^ - - : aaasemra cso annsruceonos son assenm vro usrannscrson vecors were cone nsern sno a vecor va ce onssem aserx anransormaonno eemmenca wer ceo smneeenszee c neos.-ocs enconeuman aaon' an' annsereaon usenson w enzcmoev a mo nxoew. annaran-coe sooas.useouen cao wnas se aueences were v n assem.asm seuences were vereena nex oeoneraoans s.euencn,on rea seuencnrmorumas, an o vere n vror ecnooesaa ,snmscr arssa woen ,r aenn weaasrzeeur, acnao an o m-rvenn vroranscron reaconeas.e rormeoenerae m w nuceoeono an o′ m a wnaseero′rme eemens conan seuencesromeuman aaonene. ca anaoeana, an m-′n-r concoesr waerranscronrou aon o arnuceoe e reaconnsea o urne-′-rosae .n,a-naseeo,urc waaosncororaeno erorme. n o m was encon caas onearzeasms useorn vroranscron oe ms areecennae. acv.anenreorens oen v,rora-nscre, an an c-a ms ms vere aarosee eecroore e ms wasen en . eor ss . anaeaon creenaenass c rou e auon a an sorn a −°. ,-searo-sn- nancoo ceran or-c-esosocso wenreeormua,e coes ceormo, annn,--mr assoon-rzaacecero-,^ - - w-emreeoormxuoaeenoenes acoon- w m- usn- mcronu a moc marx rano o::.:..ese conann o,oso, coesero a .re, an eanoase mxe w an aueousas n - a aesnae moar rao was o: an a a e m craeuer, conann m a aow rae rao aan o we rao o:n a mcrouc cevce.s wereaze ers an× sore an a °.ae m eoeccuenarc w oe m cu-o enc caassseuaeoonr w, serzerou a.moe ~,ncanaeormuaons caa nes waseermne encasuan mcroramua e o eecve comexn w an moe an m m-canees o,r m.ese- s encasuan- useor a su euceraseuc or m, resecve were ese nanoseaurecne esxermsensr.maornsseanre wrornns, weneverenravenous, seccanver ces.rmareaocesroeucever, an mroen, e wxrecss wonas wass oaseerv oe e ce surace oranseceeaoces as we asooc n are reeaseromever cesno a acve- an -, wc cara eoosreams. –. easzeraecerraoonnamc sze, an zeaoena o s were measure usn a eermne unson a moaevernuanns-rumenos.reeen m as esnacasnuvaon ecenc o s were on averae.. enooxneves we roen anounoe m.e averaer re conssenounoe enooxn uner . as m onamc ameer was ∼ nm w aosersnex o.– ee ceuasuurree anrannasmecc scaern .. ermosneress oerw aseon ° sa we, mammaan ces were mananen ass or u n eer -ua ermoser -a anerxmoenscern-s . mea was suemene w row ormar ces, mea wa reomcnermoser .or ermoser .maes orasns aescoe su cesem weernee ac wure on aeca-mercaooenaoncoa^ - - uscnros acnoe runnnecaxc.aonu oeecv.e. an, e aue w aecaears camera wererocesse usn ww noe sen o rn.maes ow co w.mae.nesowareownoas. emser ouneeow, weereeere aare anor samnen accornoe sannrooco o eac exermen suemene , an resusenen oow comeruer .ames were w run on aecmeecnooes an - erorme usneowo v sowaanre.ou aenrooesex use caow comeer, an anass was nen-secceramer san neounneaeeow. sann o cese we- eramners wererove e eramerorea om vnaaons.ore an s vuarcaccena anono c.eore raeeramer c exe cromcenas,s, sames w-er-e sa-ne w were us:e.or c:enrauon an --- : : uon uon an o-er-ance- exermens, : -- : : - : : uon a : uon an -- uon were us n --- : : resecve.ore. caeesesso exaeermreonms or- mce were use as sann conros, uon an --- , :--:-uon were u:se. ce:soaerom. mce were use as sann conro sn an ces were saneor mn onceeore as.n aon e ox seurrmaens,eramers wereue xao ce ano cocas anor nnm.a exe ommee arnmmeans o exeermreonas wnesreu aerorvoeocoens-u-onanmaare anse come w a reevan eca r -.nma manenance reuaons as acae,ncuneeuaaonosna anns weuree conssen woca, sae aneera oaoraornmas.nmas weree on a- s oar ceaceeuweeenor °e anare an ° anse^ - - an– exerummens.ce were accmae ae anmaacor aeasaseoreerormn musssu.erocessnore acsonaormauosr seasm.eseor smausa-se oese w-ere-ssoea wee,re weervee, arom mae mce cunemeraure comoun.oowns,e se n emeen omace an sore a -°.e roes cmens wereromrozen onr saae--se rom sncmeons were seecve cosenor soaona orvevser. na orencvemrsarmmune ces ermna anesesao mnmzeeom rso oxn-ro-m mocses.reaee a women was w saserezreorm use uner eano.nncson wasnae aeevs w scssors,ne sn n connueoe sernumo exoseeeronea c worces, an oaenneromeevsoe sernum, ane aaovmen m weamsurarnee.r oeeneeroneunmcs wnas a caorneue esv.er wea aseormunsea oraoncsa wnere a mnovneco amsee usn coon acaorso exoseever. ever,oowe en e severneneror vena cava aeo o .orrece seron o a neee aaceo a m srne conann co was remove anrusscoanr weas, anncaeever waes cavreeruan rcesence an, aearnae.eaaero surrounnssues,e an careo sever an aesons ver wa nacen ane once. was crcao ensuree enre oneress w weeruseorevene conamnaon oessue-reseneuoceouaons ne-ocoe- soursne ces. nvua m ce sraennesrson aorom mevuere ws.ereerevearressues wacerne maeseverrooesno sraner we ruer en o a m srneuner, rnsn w uerue susenson wasen cenrue a × w swnnucesor m .e ce ane suernaan was careu remove an nues a°–°, reare sooncer scare.eee was resusenen ares we, anranserreo aco m souuoen..e m ornaxue, was m wasxe w, m.o mreerecroco so, muxoen,^ - - w mncue wsa asen° c–om°ne wnee mraeu oe.e susenson was cenrue a ×oreuocesee.eo ceuaraer anoerc soea wraeree caereauoceso ceuaraer an eee was resusenen ssuer anranserreo a r neemwove m anusec caorne, an aona ssuer.er a-mnuencuaon a° ann e susenson was ce –° w occasona san,euoces.na,enreuee wa as raesnus aene ×nor munuereso aru°–°o reeee coun waseermne usn rer anass ane ce soaon an sa a sma auo oe ce susenson. aroxmaeor a vnacn ocn oaooonoo w e- asxc cerc oruma ecenn es, w a cesen-cocaaee camearonsos-vaccnaon, anenranserreo an uesrom eac mouse or mn,oowe r-acnosaeerrnue.e reesu coneceasoo sames were cenrue a sa-nn- was.erroerm,e us onre e oosceonoce™ sam-sees werxm encsean uaoo eu a wonnoerue anerm aonsoer, concenrae ano cocas: nauon as or -o , cone oeen:nau we asruan an-mouse e aon o m o-sexs onor mn a°near,oowe ear.ames wereen waseweceo wuon an m o mnnocuoaweon a roomemerauren xor mn anna resusenen ue cenruaon a sames were r.ne case oeramer sann, uon,oowree-ncuncauea won we re-soec cve-o concenraeeramers:-: naas we asroncenrae ano cocas: nauon^uan an-mouse , cone oeen : nauon.^ - - noes anes useorow comer anmmunouorescence sann memcas an e ...omeomuncans amnes enz,mes ar.esases aoso nmame-vweenor, caao numer:ssue-e rmeoxs ro meacraema-rc, .aoes--esvnse,m-a.-r.c-,^ - - -se-.aernvroeecnr,oncrosco.ecaennoces,ma--.rraure™asease-ree -.ween-, souonaocem, .c,eas-.e co, cenc, . ase·nasenorermoserce rmoser raure™ , nvroen, .ormameaoncemc,, . onuceose vana comexewnanoas, . ase . ermosercenc, . omeraseermoser ,ess eoxnuceoe ouonxewnanoas, c.enrac, . ermosercenc, .--amnoa- ermoserure .eacrc ac eser, ma-rc, . , ancenrouc, nvroen, .crame souon, o-a,- .souon s ear,am- . mmonumersuae ma-rc, .,,,’,o’-- .emeneunream,nema-aorcce,m, ..eroecnaseouoonuoonnzaoscence, ermosercenc, .narccosaaseewn , rae oecuarroes, . ron- ma-racn,oas.,am. uorescenroene no n vroever oano-a, . axresson o ms encon canae acvanroens evauaeore su ecx ca cern sesssuoane ex v aec rcv eoarsn encoronens cannrmaaer acevaaoncersoens were screene an r ssonneaoces an suseuen erenaon o ce eoaeoncoressrans.ece- w. m exresson. was- va.aremareaoc aensa wss ormar an- monocona ano - or surace ere sane wreamen w eer. m n. oeca exresson o oown m n. oecamne™ ..emrcenne™ae orm. or. osveor exresson o or wasenua areaoces ercenae o cesosveor e ne . an comareoe n vro exresson o canaex acresson o or .. vaaeneaoces ..ne examvaenrorvoeenseer.e.,n,mmo mraze weasaoucreesr^ - - woeroew snanerea wmen an w- eer mo.nocona an mo n. oro suercace exresson o em oecam amne™ or. - m waos annee e™xresso.nnrmareaocesoownransecon w , an monocona ansoo eevsanuaremar.eao.ce sam waessereraoerme usn an- an an--n. oecamne™ or. em oecamne w™ ee orr.. m . oecamne™ or. em oecamne™ .s.-- s mownransecon o - an- snormareaocesnuce a rocessn an secreon oo sroen exresson, aenoeer,eseaancoaecaa acevaeo accevsa anre aroeeonsnoe cuure suernaan. roens an conesoown eeca exress acvan xresson o a canae acrvaansneconn vro. vro roennuceserenaon o ceroenorsn erenaoon oeerm cener woeeneorrs,eeamoacoeose exc sreesmsn were caae onucn eaoces exressn - or ces were co-ncuae w exressn - or -, an-eer,ce or w sroma ces moces was evauae .-.aa are nae o erenae a are– –o resene aseercenae o–m–oces neav ue neave, ce receor+nea+ve –, oue osvee, ce re,c oeorosve , oueosve , sne a r sneosve ,oown co-ncuaon.esusncae emaooe-ecx sreemss cnesenaooces a ann srom ceas. ces are aeonuceerenaon onuce ce.ere snoawson.ero.ceur seoowrs screeennor comnaons o acvanroensa eac oe comnaonsese, werene co rmeanvaeoenrsceneaens oeerenesaeer cesor erenae ces were useorn vvoesn. cenae o n vvoever o ms encon canae acvanroens^ - - eermne usonnourmanu-aon,o corneceennraonss asna encasueramoon ecenc o m were eua moar, normazeoe conro n aoa v ser, . m-s rero-oraneconno eac m oume o werenecerou neave conro.or a oer exeromuseen.sonrvesucaernasema mn,-sn,ecucon wass w use as as a neave conr as use erum cono. coeceneaer anaocroses oa wnaesr asuraees w caroaascsuumncure us anve-,recoae s.renrues ansoae cenruaon a rmor mns a roomemerau m wasce. sames were receve o re an sna-rozen onr anass.ames we nacs an sore secure a -°roro ane orereese o-ne ex ouseoneemoneanecea coece x .um- accornoerooco asuae.aa were soware.eaa coece enenxsr aunmenaa so anwaarses a wreas ex comresseee as usneanuo.. nens . vauesor eac anae are coece rescence sanars,ua conros, er eacnvua same we.nae wereo eer ave-ara amnee sramosec vau oers wouerrea aramuseeerooracroun.araoraa onesorouce accurae sanar curv sc moeeenn werenero esor eac anae.ua conro an sameaa rove cacuaaeeromnae co snacnenarrao cnusrve os an eace anna ause accornouonacoro emonsranemoss were e eresenne same.ames erum an-xceuveesnro mmceer aenaaes ws. e ns w vevroeeece er m s oruc c an- cone , resecve .. usn aomnuc veve eora n ascevma - on ernucemraesreoowneever ouc m-s was measurenecerou rero-ora crum semernmer.ce were anoumnescencemann weacsoner wormeuc o mn an-msa a ano sses oeme mrnmeerr. mouse.,^ - - osucneercnono,a msscue were aneseze wsourane annraeronea..nece w usn auo exosurme s saens. meeurmnescoen w aecv. wace weremae mnsosnecon sowaacree.roeacroun w suane usnura.man sur aseermne ncun mcenece w conro an e omns esacen m weasurremorenn.ns, weneverenravenous,esarermar -ver..s or suocws-ucesrasneramveanon ooxn-- mceaave receve eer moc : us ourseoreman.= mce. o evauae weere aoven vro resus coue vaaen vvo, amc rec.om-noaxnnnu- mce weroerreaeas w, aner merao oor wasr maw n comnaon w anaze usn oeecer n a varousnervas an w was sow enae ces .-.reamen o a+mc mce .-.ase onesen ooserrveaeroenns,ancaunces neevxeo somuen o maure ces ssues or orans wereese a oen e non-mc nass omocenssoae cerosm wererouce. oxnnumceemonsraea co-receor exreesrsoner oaeoo c aen soeuean oo amc.- cesnever,n crcuaon, a n vareseween w or wou conesenne seen..oureamen w m n comnaon w caosonese seeromeucoonn ouce ce cesnereneaver, onreamen w w mos cesen eer or ..ne s onnereraoo,arenuce reamen w m een, ce erenaon was en n comnaon w cones, w mos ces ss. ce .-s - sur. ower. seo awr arcacamusm-urso-uroceuce c ces cane acvae ex vvo. erumoxc anases es can asoseare ces.^ - - coecenearocrooa wnaesr asuraees w caroaascsuumncure us anve-,recoae srnes ansoae cenruaon a rmor mns a roomem .erum wasce. sames were rec eraure an sna-rozen onr anass.erum,eve onacs an sore secure a -°roro o,, aumn,rceres an were measure anmus anass. nacs.amesemonsranemoss were excueromeoxc r.eame-n o. aamec o mcee w comoson msescroees neore rnes wuasn weoss orver uncon anoxcessor asaraera conrme usnver uamrans nsamnase , aanneransamnase ,amma- :erase , an aumn.. eveomen.ammas mave evove aavemmuno saeuar aansnecons anumor c emuss cenraos ssem,roucn cesaennece anmanmceurnoeus s cseesm.oeweecvser,n asee eemrus aes,sunconaecne conrues sncano cansevere m .o exoreeeas o reversnsecne, eveomen, wc ar s encon -,-, an ,eacorsor ce o ce mauraon.eecanesee wmonsramec aan,o-meeaveeroeevneerra oe aeransen ecoc se ceuarmmunn ae mce wouener seacorsmroves n nuces ecoceve an auommun.ecansca, cans enrc ces,rovn mecoanmsenc e ovenc ceesaronm vvoem enaoneoerecrecursors an acvaes eecv n o aavemmun can mmeun ceo auneracmmune an. sneumona,oe mn owos an e comme moan cm naauu nsses oseaseeas. amosn resecesoee a aee-rea aen oecern aerenneuenmzma aunne cesuemar’s soeme-roesnaeswsa. caeacm,u ws ucnerecoreeasese a o oaoens an manan enomenonnown asmcnvouonos ae s,ar., ee ac.nen. sznevo anuonun ocone wamm aae,an a^ - - ,maurs,erne o.ee.aunmaneueaorse oveomne.nn,ocvao,zaon,, an–uncounmarrou,ouonnors momuucnon. oe new ce:s-e.runna,rn.,nro eeamrer, a e. r u.oo,.asmeaarsso o a ceecre aasenn.e mmuno,,–.emso reversemcnvouonave aceve on a nramc ceeveomenare sarsromre-mc cme success. roenors s.savee caacoerenaeno ces wenommonmorere an are conseree maor source omooes oc snans o crcuann–ra+c-+ca-+s was ns ..n mce,ereuenc ennn omcnvouon ae ae o weeso s.n-can.mareoowne assessne aunance o ces w ceroenoro ssnne w sues muaramercow comer as we as exer enaneone marrow one marrowransan menannsromeerocroncmus an e ac aons.o suesa an enancemen o ce-meaemmun can one meavrreowranesraannsoaensa noona ove auvse eneec.meurseonreo an ae recen, we an anaoous an enancne ce receor reero ,mrovneuncona o ces ouaon. re reman crcae unme neesn an aen unern reucceans ceosea sunneraconsne anmus, mecansmsnuce ceev ouu coueene an,oena,acorsa coue useo acrossmcnveooumoennn ouse oe mcem wce mrecrroeevnvoursonmerno.emo ccomes annn srosma ces an saa sne-ce an seuencnu e a.,aa mas o ce resocaeranscromes reveasncmmune nces annera ceors an mmun , –.e .ecause cconsne aavemmune resonse.neracons w mc eea ces, sseroucons manrven ce-ce moces anmc eea cesu n ce-ceneraconseweeneveon u: a scaaeramewor rn an were anaze, usneu aa e a.,neraon oeone roemro svaaa omcs anass.a.eos,– rom comne exr e a.,eone:nerrn ce–ce communcaon anmenssoan o mrue e-s au.,unmnaan–:reuceeonre cso amneaxeesw.aao.rroeorac.ure-,curae–^ - - s acnuarennaormwaaon re.sourecre as.usan.oer coomsos,ona– canes, aooan recourcoraee saaneraconseween corcamc eea cescs a onnnerceuar oowne sar omcnvouon wasscovere, noue-neave cesneraconseween ms a wereasere was no aaren canen eone reore aoossn anorue-osve ces w an s.-.ence, mc sroma sem ceoo eans-erenaon o an cs aneeeon oe – , c uncons aruonnna e a.,amars o ce an.a.mmuno., e ear, c-eenen saes o ce aece mcnvouon,oeermarnneracon anas eveomen.ne moecuareve, receor-an mocesaes reveae mue snanawaseweenmc eea ces an wcaseeneesccrease w ae..ounereun- -meae snan, c re as crcaor ceroenor survva, wasounoe reucen osw,n moces werereceo aona receve sncaness anoc ceevseroeamme snnan.o.srevomusc rensveoarucon,ureer uneermscoorrnanc ae ooenaeanecn earroarnsea rneaenoenra anon c oonreme ce an cnomraarmmecn re,uarremcuarn oer mceoownone marrow exresson o an enances enorsacorenns e a.,nramc .owever,sneracomc recover aerrraaon..x.e.,– rouce ervascuarrn wase noeeceereecause srmar reeneraon.mmuno oassne au musaur e a.,mus:e nex revous resea .ev.,– .ase onese resusn comnaon wes rc,reeacors, cans seece-, , anoc snan,orurer resnonn ae mceonvesaeeseacors cou reversee eec o aen onemmune esev.er o ,, an m oevermrovesmmun ervascuareroaes-ssec scseemvce arm onsreaonens ceaeanconrs aoe r n womes ucon n ese o aea ces or numerousmarmens ansruessue arcecur ccounore ereore consere a snec aroa e cause mcnvouon. cans eecve assne neeor anncacanmvuosv aerceecveurre. oneesre naocrmoras coo ann econos,c na svee,^ - - cee osneo ex ncoenoenraoc ws, eoweveera,s ceesnve nro.n-s umnuoe sssuesueoe enoeaarrer. crcuaon, enoeaenesra rucure, caracerze sowoonera ons, ane asence o aasemen memrane,ermsrec eaocconeserwoueenene cseras aonnsne mauorcneesver sarnruesno ea a e.n,oema coecesnerac w – .ever aonaoss varous cees caae osr.eseneaoo ,o cesvonnran e a.,omn an ceuarracnm noes n anens – ,erono e a.,nen-seccrmar acv .a.ev.mmuno., ver..mmuno., – an manans aaonu oncona ca ces wne avance aeun e a.,amars onnever.omu.r ac, evenn – .s susane aaa urneaeveomen anuc ce.roecno..,o suor exrameuaremaooess unerscor an auseasesoacaeeeveomen esever’suncona an srucura caac unconaeaures o exrame ouarooem ceaos woeenc n seeeme anreoneen eor a c,e rneseurevo moecuar an oo , – .as,n vvoever o nanoarce -resncnaumans. moecuesoeaocess ecen an rous m e a.,nneere suae nanoarcesorareeever o eraeucsnoerenes onzae cv .orese reasons,ever was cosen as o cesnever. cansene ,- , an a se- o ecoecren caeer maura aon. acorsor ceeveomen, wc areeee w mc an. cans ennse ormuaroane oro mucon-e oncooe eere a emons oca a wcvenoaecorarsaermars murnse.ea aonces ans. ro-en. exre.sson sno mwosuseuoeresacoecncees.ma-easenen sa annnu wanas usceaonr o surace caear, m.. sows exraceuar c oeneae ce memranes. an r secree m-ranseceonecenraons oooca acve-e , resecve.aa are mean s.e.m. aoces aseermne - aness. n =neene vaues were cacuae usnwo-ae unare- s nransecon exermens.oownnravenous amnsraon o .-.., canseece ces resemn cesnevers o amc mce^ - - ces ancoaunnseraormec sannse c-aceure a cross-s seecuoennc on oesever-arencma saes o ceeveomen, wc can ceroenors a varous acor exress seneae anazn canoncaranscron asence o aonmuas,e wrnsc res.ue-n.eeenseer caeosn a oso a unrmerwevne recomnaonne .-. ,everse reerore enancecsanmsm wuenree rnesereosnsees anr ceeamuennconn ae mce o aaer anarmas. enancese comromse ce resonses rm onssen wrornns, weneverenravenous,e s reeameenve or, a ane mmmun eoxcoremsseonen wa ms sceecca wee oss oervenver ces.. caenemrove an-umor resonsesn a w roroumornorsn ae mce r meanoma moereae wmmune cecon uvanesrueanmenn onc areaese an smurvva .. nmrove ce res as caene wee vaccnes aso resue numerca anuncoonnases ‘ arneuv aennancer’e vaaseccnne na revse ces .. cans were aeo . onses w . wees o ae. emonsrae cevenracan reeevanuncona caac an unue anaom oever, cans an-umor an vaccne resonsems.roevcemanensscan, cemmcaunnsounn ae mce,ncun enance ecoceveomen o cerecursors ae aroac enaese ce reerore never, umae crean armve,uversereamen avosnee asoenecnea o a sevmeures. sneers ecoercns oso cenoaneoreeeoe sae,s rerorammn anoes norer auomm amens or ceuar evenceaar unnreae anmas.e resus oerromsn an. een vvo enneern o cemmun can eecve couneracmmune neccrenasennmmuneeconocaeesonsen aurneoe oe-reae aucuaneounsu-muomrormmamnuanon anreamen wmmune ceconnors^ - - anram-e axnressonme mn’esanoosmaa, coesonn,e.-ce w wearsennocuareov sue cae w ×5- cesnarearxornn.umorrow w cuaneous measurn w a caers usnewoareser as monorea × w oeumor exceee mm encuar axes une areaen an-- .,oe, an.or conr oo ana-- cone:.,oe, a oce werenecenraeronmser oe, anor conro revouse ea anas aerumornocuaon as osc erve ceconocaauea reesoens eencaucmo or-eear cnom aoes monsescreerennncreasnmmune reuce aavemmu ce, a murne moe exn ae-reae, onssen wn wreavs eosusa resoresnsees. o . w an–-- anoes varous moes,mmune ceconnor sucu w5asess eecveorumor eracaonn ae mce -aneo.usumonro ocuuareow wn ×oun o mvaceu wmasn susan-eaxre assennu meanoma cess. , wereas no resun an noceae cnca ae reamen . mner acvn ae anmas, sncan n seurvrovua o.. oseser weeor w aeees mnc=e- awnee a- soear aanem caonsr woasroreuae wa wsrea-soras n=.oownreamen, eacrou wasnocuae5e w em s ne ona an suseuenreae w an-- w × - meanoma ce ana .-.umorrown resons aenoomm ona .- ora was measurea an overa survva une ceconocae exermen an s.- se roa were evauaesees.- rs a con exermen.umor reecon was oserven ou omnmroavsem aneno onver-erm s-.r,e.a,uervv aanmnas o. mce anreae w.aen-s, a sncan emonserane aea mece co emxosnonsmesncrsee aear oeer,eseaa resons env aerem cmauane. oncreasn an-umormmune nmcmreuansnaccnaonesonsen aurneoe oe-reaeecnenave^ - -mmunzaono re esvaounaseen aee e mcacce, a o murnee c moomeos exonsnescreerennncreasnm ae-reae, reuce aave amuuncu wanaes esase. n comeeoo ruu eunsmm n's a wuen uea vasn aonn a,e wees, mocoew weerem onmeu onze wroen emuse emusenncomeereun's auv rwoooseroses oroen emusen sucuaneous awan , .ce werenece w anen o.er mouse.e ne o ses one ces,necn. m a eac seoa aer eacnecono avoeeea waase oeens eemruesonn.e suoocsuearnneoeucs sona oceoro secons s amnsere as aermmunzaon w anen e anen emusen as a sne sucuaneousnecon w muson.eoosersven erearnaco . m o emuson, a one se one sernum.erum, u o or seen sames were oane as aerenammunzaon. oaro an o v vaaccccnnaaonon e rxeseornses aroxmae ooo mens, aencaemeonsos-vaccnaon, anenranserreo an wa-sco caoeeceue w.e coe-cceoaeo coa saamreuse wserreom cen eac mouse or mn,oowe ranserrne resunasmano anoe rue a mouse anoes were measure va usn aousen rue.n- onrexnc, , accornoe manuacurer’sro - nossanecncaucaes, w avera oco. sames wererocesse ooca recae. sames wereeac vauroesun o suecrnaccea usuncaees aveerane o reoreeacorro eac oe m sanaruer on conon, ane sanar curve was un reressona was useoreac-cacuaon o anoe o aosc wererearenencae mmeeumon m meansonnes asuoev ae,a mnsousres. e s seen sne-ce susensons acon, -.en,e sne-ce sus urace o a-m ce sraner e suernaan was re enson was cenrue a or mnues an ermoser a °moorve.. menueso,oo coewes wer ceensreuao an ann rem mov oa oe susesrnauaner.^ - - m cuee c uue rems were was n me aen once w um an senm-ureae an wo mce.×um6an o seenno recsus :esenroeme e wace msonusees were a ur encr a ana concenraon o mor eacee.eozeransornor coca , was ae accornoe manuac o oursaer.en,oursaer,e c urer'snsrucon rorococ wrueasn were coece an wase w uer w nauon an surace ano s an-mouse , cone oeen: uer anenxe ane annor mn a °.es were wase w a , a rmeaze usn a oermxaonermeazaon souon souon,ooweccornnraceouear m sanaunancurer’s mnnsrucons.es were wasenermwas cone anoes.na,e c ,° usn a coca oe resecve sa es were wasenermwas souon an susenen a ecnmnanueor.ames weorwe wasomee,e rre.susnaenses wanserorme uuer an acure on a nerou o aemmunocomeen mc snowo v soware. a searaerou o aemmunocom e wasreae w n= anreamen, eacrou wasmmunzeeen w mce o wvaasurmeane w w c eommeerenu=n’.so aouwvannncomeer oenuna’s a aunva snuseuen oronvae a.ooosoewrnmmmunmuzanzon w ovaumn w w ov aon, mce werereae oer:aum eraen- oroaemrev rre awen aesa an rev ceeae aaav:e re asnonse wase evaouaeerouc.on o. anarss ercenae ooueos eaer : ve ces ..eercenae o was meaesurraemer-secc cesarveseromereraoo, seen,ver, anmus oun, we ceoms,a. arseon m o. cee : eramer-secc cesnoun mce - m an m e, weesreae w, an ae m mcen comnaon w nanoarcee s sownns-. sascarea sen wca em ercenae ooa ces an ces seccor n:re waaesr^ - - o wservee eomre aerou.reae. woe-secc ce rearoveoe ae mceroureae ra eraon an cone secreon wnzme zm,-, an- were aso sncan erore aeroureae m an m. ex.ee mnccreeasreeaero w m n comnaon w -eramer-secc cesneoo, seen, anucvoenr r oea : no receve m ..reaer reaverooroveoe conroroua ces wasounnever comareoemus n oeramer-secc oserven , w noncreasenroucon o suc ces seaer.. re-reae w aenc-mars, aormee cmourrsoev eex vearcmcenne r oes vonse oserve wen ae anmas were aenn w-e mce o v accne resonseecne waserorme. neave co arous aeso wees w aee vaccne sowe a cear . r arneaone.wreeeanm aene anerooron o vaccne-resonsve cesne seen aume o mce w was aso sownoo mcenreae : eramer-seccmmune resonse wees reave sncan ee w n eanceec em o cere-ammeen. ae w. vaccne- resonssesronr ooee vaccnaon, oservnreamen .-.s enancemen was er anmas comareouc- we, esasencaors evence ncrease seen ceuar an -s asonc ommune acvaon or reconsuon ..reamen w seen anoosrreeaamsee.resen.cee oe vaacecn ane-nenuc eex,osuresrou-seocuce r ceessnoe een–en nav+e- nao-vmeem coers s werenreseen cnee re sereeonre.nne w s, susaunan an m aoere- reamen,owever,ncre ooun mce comareo ae mce. ..onves aseereuenc o nave cesne seen o ae anmas exermens were reeaaee w we eereresne eveucas m were asr oruae reecoom a snnaner comonen,ese o- an - s.-.marorevous sues on rec oen euvaens auvan, on-reamenoses o er we omnan- as a vaccne o vaccne-resonsve cesne seen.owever,e- sreanmecnan nnocre raesseune a anunncraenacsee^ - -ne narvee ces m or crcu coamnnaon.s-ssenc acre cemoneens wnenernesraromo con, acs oserve w -rmarnuceroeraon o maure ce suses.e aras, were as m no recauae an oe oserve eec r sneacors o evere emrove vaccne resonse, ae anm s s.-.s aencmaror exermen o vaccne r as werere-reae w -s.me course o wees w aeseonsee veacccnnee w sasow oeser av cee.ar neaaenven co wrrea-one mewcee o varous aes rooron o vaccne-resonsve cesne seen. en ae ane w -s exe sncan enance ce res .ne-ear-o anmasreae anmas, we resonse anno onses comareo same ae w-e . weesoerooca a wa cans oserven mucouner anmas ≈ anmas reveaea cesre, =. ..nass o senocesromese - uon anen re-ex om--reaerousrouce ereves o- an a ecoc exresson oosur,ea,n anose-ronm ceonvreorsr aouosena. va.e sesrea reesuos ennacnacee ane vuanccconne- onuece cemm reunero.resn s oueres msc ae,ecanon s oncanmrovemensn an-umormmune resonsesnmmunocomr s aroac maransenoos : omsenvuas. - nave+cceanss oseorvees uzeonraeameenm wmunosm muaor eecs anncreaseresence o o nove ces.o exoresoess, c a resunarromemooess oxn- / -mce, wcacemc an ans emoeomozous.-oxn-- ora- / -moeso noa ae,u une oer moes o ceecence.., uncona maure ces caneve aeneceur,erarecuecars aenc anu m cece m,auueraoon a.nnormaca, some r aecom censa woans a cnonerrmee.ra ex waanss aonm.necsaeursee os,roro eac exermen,e asence o arencma was anaze a a asneror exermens anenever earoo aer n earreamen saea, aeroses ane seens an an comemena ar co smnee-cee-wreoenrea mmeeno csourse.a.,s earose ass usans aower ceomnnenr^ - -ream.eno,nonuc+e sarnamsm wune cneeracveornsarernocmmea aenreac vesses were oserve . rouens cenruaon an an useverssues wereensoae was anncreas aze va+ow comer.ne-reae mce,erenraa ene asoue numer o ces,rven e emerence o a newver nrenec-cema+ +ceouaonaace an exresson.. ressoae-semm ouneve creasrencma ceroenors reoo cess we osens cenruaon over ce susensons an useuen, r reoce w ra an-mouse . er we, eoscence. or mnuesecve anoesn were aen aoa voume o an sane oeen, aens.-e anoes usencue an-mouse - cone., -,,rmuouasen-an-mcone ,oeen, an-mouse - cone va eeoscence was emooeuse , cone oeen. euor xae es were s ere manuacurer’sroocoo excueea ces. wasewcea wne w resecve an mooos aonr so mren a on a °.useuen, ces were m nozzeno c on sorer usn a e once unr e.m mcrouesa werere-coae overn w. an , cesoeorwoncess oocen. ar reearcaaoenr oe scnaee-c:e m scuesens,ons an sorn asescre aove, ono axromum conroer ere manu recae: mce wereoae nee eaensv.emsr.ea rcurer’srooco usneromummmeae sueceo rever esun emuson was recovere an rarrearaon, aernoseer manasncuracounr.er’susreoouceon. seacs oncueena cranscsroaon an rares unerwenare-en seuencn an  on a sne ome an ane.aw seuencnaa unerwenrocessn an umnaovae m - mm usneeanerenexenomc anmenoe mouseenome euraaases wereeneraeoroo anmus as, verson... eneereuseeura vneesaaa.or eacmeon.nes were an useorownsream anas seuraarcesasn_vnee.m unueeaures wereeece,e asn.essonaan, on o c mesoc won mroare couanns we arne coesnssearneor^ - - suerners, an emasos.nsne scee armonreo ac-”aa,”n seorumeancoeno wra cso anoeeer same usneau ne-ce seuencn oeve can. ne-ce seuencn orarencma reeranscronasnc ce c everarencma-nran ces soweransc users, exressn vare ses oneae marerenes an raronaonacorssncave oeren saesn ceeveomen .-. reaonss,, exror-ace ceua sra sensa ar reeuvremeennso, anre ceommasesase onnownrecursor-rouc ceroenors , asonown as an a men saus.asencues ear uncomme cerecursors saes, caracerze eroeraon o ceneae-com w aeenenc onoc snan.ase encomassese ocuroerameees an a saes, were ces ex aereenenc on saes,ur s an unero ene rearranemen.ase sansrom o snan wc ceneae-comme cesroeraen resonseore- or marers ans ans c evaernacuaersocs oe eoceenenc. cansoun cesa exressneae e ac oeseeveomenaases.. ces,e eares ver ceewre cceursso crasnuree wmnus c.uns ceruser, excreasnses oser,v reese emxren a numer o ce seccranscronacorss,nne we nau sson ooase.sransonsarerven eocawa, anraranson o ces roenrovnocans.rovn - mmcsesemc senasmusas a va seerne cuser cesowarse ceneae.nase o never nce, se oss reconzeoave 'maser-e' ceeveomen, no secc overan woc snan, a we-e acv.e,rou er coecve acons, cansoun cuser ces e ne enseme oacors esases ceen. reerreo asn,ec,cxe asnc se oeseases,ncunmoaso ear wrco- a ces,ox -a,ex,, an,n anmen we caracerscs o , a anes.xresson oeseaswosecreasesn ces o cuser unrsn w ceeevsoocaroresson oro- cesnoase .. enes, re eomen,oc snans asonsrumenan acvan a se os crcaerorer uore asuaasneeneenses.amoenneese c,ee coenorna ane e uxmreasseon a ocvaaan ancc.^ - - noevaeanso a a vearna roveenn eneasuresn.ass a cceevroeennoarrs, mov renresrsonmaseoase,o an , wc serve essena roesnnnaemo ces a e exresson o ouna cesn cuser exresseseree n nauraer ces. cans exressonaern, wc was no oserven cuesu no or .ssnc as cesransonromas sers an,sncave oneae commmen . , suceasnsn asoe oe sese cro evease s ma ce unsn. er couse.r reecaonm co-neaxorne,ss wnr anraenes enerane reerore an-seecon.oeec sns cs essenaor e vernraarencma ces, cansncor o acve recomnaonn er anass.ecause cans anca orae aeece seuencesno ese eareveomena saes e caurnncomee recomne surn reerence an suseuen, re reeroreroes were ane we m ara recomne seuences eaneeaa w asoen unroucve or ,e e a., : anmmuroroerncusonne sne-ce anass.,ae es.,- . nooun varaeoman seuence anassoo.uceccs^T ^ec^^ss ;sVal tneersubtamerpotnodoh^ a c dderre^o^DV -D- AdNR dc e ^^N ar r AaVer^c^ecAD V d ^N DU H MF- ECNAEAUAACCAGTATAACCGAAGTCTTCACAAATACGAGAAAGATAGGGCGTTATATACCATTGGGTGCTTTAAAATTACGGTTGAATTTTGGTCTCGCTGGATCGAAGTCTCCTAGTGGATACTAGAGTGTGAGGATCGTGTTCGATGCTCACAGGAATCGCTGTGGGGACTTTCCTTCCGTGCGAGTGAAAAGCTATTTCGGAGGTAGAAAACTAAGTGATGCAGCTGGATTMd^erev- ESMoLcexo ^ e LUCFCGEANAGGTCCTCCGAACATCAAGGGGACCGTAAGTCCAGGCACCTTTTCTATAGAGTATCGATGTCCTCCCGGCTTGGATAGCTCCCGACAACTTAATTCGATAGAGTAACTATGTTCTTGAATAAATTGGAGTTCCTAGATGAAOGGGTATTCTTCCTGTCTCTCCGACGTAAGTGGAGTTCTAGTTTGAATTGTAATCTCCCTACTTGACATGTACTCCACCCCACCATCGGACGATTTTGAGATAAATAGCATGTAGTGTCCATTAAAAGAAATGAGTAGADN Nr^aerA NAFDsUsAeMcc- ^LCCTTAACCATTTCCATCACTAGGGACGGGAAAACTAGGTTCGACTTCACTGTAGGAACTGTGGTACCTCTCTCAGGAAACATCAGCTCAGGAAAAGATGCAATAGATCGAAGAATTTATGTTTGGGGAAGTTTGATTGCCAGGGAGCCTGACACTTAGACCGACGAGACTACTAGCACATCGGAAAACCTATCTTCCTCTCTTTAATCCAAAGGGCTCTCTCATAGTAACAAAACGACGAACGCTATTCATCTAGAAAAGAGGGACAAAATAAGAGGCAGCAAAGD M N^:^sro4 TGGCACACCCTCGTAATTCCTCCCGCCACCAAATTGACAGACTTCGAACATCATTTAGAAGAAATCTCTCACGTGGAGTACAACGGTACGAAGAAGGAAATCTACAGAAATGGAGATATGTTTTAGAGTATGTTTTGAAGTTTGAAT^ea eor^ELBATGGGGTGGAACAGACCGGGGTGTGATAGACATTGTTTCTCTTTAGGCCGTTAGCGATTCCCGGTTTTGGACTAGTCTAGGATAGAGAGCGAGCCCGAAGATCTAATAAAGGAGAGGGTTCCGAAATTGGAGTTACGG ^ W- D - N AVEASLLCUCFTATGGTACCCCTAGCTCTGAGTGGGTAAAAAGAGACCCGGGTCGCTAGAAGGTGAGCACGAAGGGTCATAACGGTTTCACGGAATGGGGTGGGTGCTAACGAACATCTCGTGTTCTATACGACACGATTTTCACATGGTCTGCAAACAGCCCTGGAAATGCTACATGTTCTACCCATAGATTGAGCTGAACGTAGAAAGGTGGAATGAGACGGGTGGTCCGGATTGTTCAATCAGAATAACCACATCACTCGTCCTGTGGGATCTCCTCAGAAAN DU EH MNMOLMCCAGAGAACDN NAAAAGTGCTTCTATACATCTAGCGCATCTACGAGGAAAAATGATAGGCACGTTGCATGCATATGTATCGGAAAGACATCCACCAGGACGCGTGTGCTTCCCATCTCCTCACGAATGGTAGGAGAAGCGAAGAAGGGAGGTCGCTTCCCGCAACCGATACACATGGAGGAACCCAGTAAGAGTTCACGAGTGCTAACCTTTTTGTCCTATTGAGGAGTTCATGCGCATTGGTCTCGTCCTCCTGGGTCCTGTACCGATCGCTAAAACAAGAACAAACCNA ACTCUCGATCMCCGACTGGAAACAAGAGATCTCGACCGGCAACTAGAACAACACCTGTTAACTACAGTTTTTGTAACTTCTTCTCCCGAGTAGTGGATTCTGTTTAATGTAAATCCTACTCACACTACGCACACCGAAGTCTACGTTTCCAGTTGAAAGAGCTATGAGGACTAGTGTCTCGCCGACGG_AACTTGCTGAACCTCTAAACGGACCTCCCATCCACTGGACGAAATAGGCGACCACTTAGGACTGGGTACTCTTCAGAAACTCAGACGTAGGAAGAGD M4NAELBCAGTGGGCGCTCTCTACACGGGGGTACAAGGGGTACCTGAGATAATTCAAGGTCATGTTCAGTAGCTCAGCTGTGTGCTCTGCGTCTGCGGTAGGATGTTGCGACTACGTGAGCAACTTCCTAAGTCCCAGCTGTAATTGGTACCCCTGGACCAACTGTATGCACCCGAATCGTAGTACCTTACCTCAGCACAAATCGGAGAAAACCTAACTCTTCGCATCTCTTTCTAATCTCAAAAGGGGACTCTCCTTCAAATACCCTGTATCCTAACCAGAAAAAC ^e W- D - N AVALLUFTAN DU EGAACGGH MNGAGGAACGCGGGGCTCGGGAGTTTCGCTCAAAGATCTAACCGCAAGCGCAGACGACACAGTGGCGGTCCCCCACATCCCCGTACAAACGTAGACCCTAAGAAGCTAATCTATCTTAAAACCACGTAGATGTACAGTGGGTAGAACAGGACGGGAAGGGAAGAGTCGCGTCTGGTGGTGGCCTCGTGCACAGGGTTTATAGGTATATATTTGGTTAAAGACACTAGTGATGCGGAGCTTTCCTTTCCGTCGGTGAGGTMOLMCGGTTDN NTTTCATTTATTTTCGGTTAGCTTTCTATGACGCAAGTTGT_GCCGCGTTCGGCTCAGAGATCGACACCTACATCCCGCCGAACACGCTCCTGGTACGGTTTTGGATCACTCCGCGTAGCAGGACCGCTGTGCTCGGAAACGAGAGTCGCCACACAAGGTATCTTCAATACCTCCCACCCCATTCTGAGCACTTCTATGTAATATTATATAACTACTACTCCTGTATAAAGGTATCGTCCAGGGGCTTTGCGCAAGCCCTCCTCAACTCGGNA TTTUTGCAAMTGGTCTACGAGCAGAAAGGTCAAGCGGACTTTCCGCTTCCTGGTGGTTGTCTTCCCGATAACACTCCCATACCCTCTGCATCACGGCCATGAAGCGTGTAGGAGCTGCTTTCGGGTTCAACGGGACATGCGCTATACTCCAGAAATACCGTAGAGACAATCGTCCCGCACGTGCGAGTAGATAACAAAAGAGTGTATAATTAACTGAACATAAATTCTGGATCCTTTATGGGTCAACCATCCAACGCTTCCAGGGAGAGATAATTCTD M4NAELBGAGTTTTTATCCTCACGTATAAAAGGGGGCTGTTTGAATACCTCCACCACTTCCTATACCCTACGGAGAGAAACAGGAGAAATGGGTGCGGGAATCAAGGTTCTTTGTGTCGAACTGGAGCAGAGGCTTGCTCGCGT_CCCGCATCTGGGAACACCCCTAACAAAAAACGAAGCTACAATCCGGTAAGCGTTGTGCGCACTTATGTATCGATCTCTCGAAGCGTTAGGGAACAACCCCCTACATAGATAAACAAGAAACTATAGAGGCTT ^ W- D - N AVALLUFAGN DU ETCCACGH MNATATTAAAAGCAGGGGTTATCCTATGACAGCAAGGTTGT_GCTCGCGTTCGGCTTAGAGATGGAGGTAAGCCACGAGGTTCTCTTACAAGTTGAGATACGAGAACCCMOLMCACTGDN NTTTCATCCTCGCATTGGAAGGAAGGGGAACCTACGCTTCCTGGTGGTTGTCTTTCCGATACTAATGCGAATGAACTCATCAATAGTACAAAAGCGTTAGCCATCGTGACCTCTTACGGTNA ACTUTCAATMAAATGGGTTCGTTGGAAACAGGGCATGTCGTATAGCCTCCACCCACTTCCGTATACCCGTACGGATCGAGCAATCCGAACCACCGATCTCTCACACCTCTTACGTCATGCTCACTTD M4NAELBCATTTTAAGAAAACCCAGTTCTCGGGAAAGCGGAGCTTCCAGGTAGAAATCTATGTTTCTTTTGATCTTGCTTGTCATTCGGGATCTAACGATTCGCGTTAGTTCTCTGGTGCTAAGAT ^ W- D - N AVUEASALALGUAFAGCGCGGTCCGCTTCCCTGCAACCGATTACACATGCGAGGAACCATAATCCATCACTTTTCATAGGTAGGATGCCTTCGGCTGGTGCTAACAACCTGGTAGATCACAAGTTTTCTTAGGGGTTACGAACCCCTTTCGACCGTCTGGAGGAGAGCGAGTGTAGTGGTAGCTTGACTTGTGATCTTCCTAGTTGACCTGTCTTCCAACCCCCCATGGGTAGATAGAACGGTAATATGTTGTCAGGTACAGTACACACTTTTCTTTTATATGATAACGAAN DU EH MNMOLGMCACCCTACCTDN NACCTCCCGAGTAGGGGATTCTCTTTCATGTAAAACCTGCTCCCACTACGAACATACCTCGGAGTTAGTTGTGGAGGTAAGAACCTGCTGGACAAAGGTATATTTGTAACGTACTCTCGAAGAAATGGTCTATGGTAACTGATCTCACTGCGACGAAAACGAGGTGGACTACTCAGGGCTGCGTATTCTTCAGAAACACAGCCAGTAAACTTCTTAGAGTTAGAATAACCATCTACCAAACACCATGTGTCGAGCACAACTTTGAGCTTTCGACCGAATANA ACTCUTTATGMAACAACCTCTTGCAGCTCAATCTGCATACCCTCACCTCAAGCACAAATACTGAGAAACAACTAACTTCTTCGCATACCCTTTCTAATTCTCAAGAAGGGGACATATCCTTCCATAGATCAGAAAACGAGATCCGGAACACAAGTCTTGACGGATAGGACTAACCATAAGGAACGTCTATTATGACCGTTTCCGGTAGAGTAAACGCACACAACGCCGGATGTAAGTCTCCAAGTGACTAGAGAGGGAAACGGTCGTGTCTAGAACCTAGGGGTTCTTCGD M4 CTNAELBAATGGCGGGGGGGAGAAGCACCCGTGAGGGTGATAGACTACGCACTATATAGTGTTTCTTCCTTTTGAGAGCGCGGTTTAAGCCGAATATACCTCGCGATTCTTCGTGAGCTCATGTCCTTATGGTATGAAGAAGCATCGGTGGGGGGTCCGCTTCCTGCAACCATTACACAGGGAGGAACCTCAGTAAGATGTTCACGAGGTGCTATCGCTTTTTATTCCTATTAACGGAGTTAATTGCGCAGTTGGTCTCATCCTCCTGCGTCCTTTGTGGATAGCCTCCC ^e W- D - N AVUEASGLGLAUGFGTAACCGATAGGTTAAACCGATAGGTACGTCGGAGTCTAGTGAATGTCTGAAAATCCAGACCGGAGGCATCAGTAAACGAGTACAAGTTTAGTCAGAGTACAAGAACTAGTTAGGCCTTGGATCTGTGTGTCTAGTTAGCCGTTGTATGGAACAACCTTAGTTTATGGTGCTCCCTTACCCACCCCCCCGGTATAAAGGTAAAAACACCAGTACCTGAGCGATAAATTTTCCGAGAGAAGACATAGACGTGGCCTCGTGGAGGAGAN DU EH MNMOLCMCCTAGCATGTDN NGCAAGAGGGGGTCTACAGCCTCCGTGCTGATAGAAAGAATTCTCAACCAGGTCTTAGAGTAAACGCCTTATCACGATAAAGACAAGCTTACATCGCGACCTGTTGGAAAAGTAGAACTCCCAACTTTATCCCGAAATTTACCTCGTAGCCTTTCACACGACGTCATACAGAAATGGGGTACGCTTCATGGGGGGCTAGTTAGGTCCACAACGAGATATGTTGAACCGTGTACACCTACTAGGCGGCTTGAGTTCCCGTGCCAAACTAAGTNA GTGTUAGAGTMGGAAAACTCTACCTTCCCTCCTATCTTCTCTACCGTAAGCAGAAGGCAAATTGATGCGCGCTGTTCGGAGCGC TA_TTGCTACGTTCTGTATTATTATCCGCGTATACCGTGCACCCAGGAGGGAGTAGGTATCGAGGAGGTAAGGGGTCACAATCGATTTTTCAGCGAGGG_CAGAGGTAAATGGCTCACCGAGGAAAATCTGCGTTCTGTCCTATGTAATTCTCAGACATCTACCATTTGCGGTTTTAGAGGTTCTGCACGTTTCCGGD M4 AGNAELBATTGAAGGTGGAATCCTGCTGGTGTTCCCCGAGTATCTATTTGTCCACTTCCTTCCATCCAGGTATCTAGGTTCCGTCCACGACCGATCCTCCCCAACATGGTAACGCTTTGCTTTATCTAAACTCCTGAGCCCGCAAGTAGAT_ACTCACACTTCTTACTGATAAAATCAATCCCTGCTGATACGGTAACGTGCAAATATTCGCGTTCCTGGTGGATCGTCCTCTTACGCATTTGAGAAGGAAAGGGGGAAGCTCTACGCTTTCCTGGTGTGC ^ W- D - N AVALLUFCTN DU ETTAACGH MNTGTTGGGATGAACTATCATTCCTCCCGACCCATTCCGCGGAGATGCACTACGATCTATATGATGTTTCTTCCTTTTACGAGCGCGTTTTAAGCAGAATATCACTCGCGTTTCTTCGGTAGCTCAGGTCCGTTTGATGGGTAAACGCGATGATCCGTGTGGCACACCTCTTCAGCTCATCTGCATCCCTCACCAAGCAAATACTGGAACAACACTTCTTGATACCCTCTAATTTAAGAAGGACATATCTCCATAACGTMOLMCGTTTDN NTTATAGTCGTCAGAGAACAAGTAAAAGGTGTAAAACAACAGCGTAAAAGTACTCGTTTTGGTGCAAGAGATATCAATGTTATCGACAACCGTTCTTTCCTGTATATAATAATTGTACTTAATTGGAGGGTATTGGTTGCGCTTTCAGGTGGGGCTGCGTAAACACGCACCCGTGAGGGTGATAGACTACGCACTATATAGTGTTTCTTCCTTTTGAGAGCGCGGTTTAAGCCGAATATACCTCGCGATTCTTCGTGAGCTCATGTCTTNA AGGUCGATGMCATCCATGGGGAGGATGCATTAGGTAGGTACATAACGATATGAAAGTCAACACACCGATTCGTGTAGCCAATGAGACTAAACGCATTACGTTGTTCCCCGAGGAACAACGAGAAACTATTTGCAGTCTTTTTCTGGGAACTCCTTGAGATAGCCCTCTCTCTACTTTGTTCTGGATTTTGGATAGAGGGGTAAAGTAACCGTTGTTGTGCAAAAGATGATAATGATTTCGATCACCGTTTCTTCCTTGATATGAAAATTGGTCTAD M4NAELBTAGTGTCATTCACTGAACAAGTGCAGGAGGGGAGAGTAGGACAGAAGTACATGTCTACCCAAGATTGACTGAACGAGAAAGGGGAATGAACGGGTGTCCGGATGTTCAATAGAATAACCCTCGAGGCGAATTCCTACCCTTCCAGGAAGATATTCGTCTTACGCTAAAGATTGCTCTAAGGAAAATCAACAACCCGATTCCTGTAGCACATGAGAACAAACGCGATACGTTAGTCCCCGAAGAACAAGCAGAAACCTTTTGCATGCTTA ^e W- D - N AVUEASTLALTUCFCATGTATCCTGAACCAGAATAGATACCGTAGGTGTTGCTCTGGGTACCTCTACAGTCGCCTCGGCATGAGTTTCTCGATAAGGGTTTTAACCCCCATCGGATTAGAGTCCGCACCCCCGTGACAAGTCACGTGGTGCTTACAGATCGATCCCAACAGAGGTTTTGTCGTCAGCCTACGAGGGTCGAGGATGTCCACCTCGGACGTAAATGTAACGAAGTGGCTATGGGATAGGTAGAN DU EH MNMOLGMCGCGTGTGATDN NGGGTTAAACGCCCGGGGTCTAAGAACACCCGCCGAAGTGAGTCTCCACACTACTCCGTAACGAGCAATCAGTAAAACCGAGTCACAAGGTTTGAGTCCAGAGATACATAGAAAGATCGACGATGAGTTCCGACAAGCTCCGAGAAGTTGATTCCCGGACTCTGGCGAATAGACTGTCATCGGGTTCGAGAGACGTAAAAACACCAGTACCTGAGCGATAAATTTTCCGACTGCAAACAATNA AATGUGAAGGMTGATTGGTTTCGCTTTCCGTTTGCTCAACCCAACGATCAGAATGCTATAAAGGATAGACAGGGAAATGCGATTACGGATCCAAACCCAAGATGCAGCTCCTTACCCACGAGAAGCGGTACGTTTTTGAGGGTAGCATGATGGATGCTACATAACGGCTCTTATTCACATAAGACAGCTTCATCCGACCACTTACCGAGTCCGACAAACGAGAATATAGTTGGAACCCGTGCAGCGAGTCCD M4NAEL TBTATTCGGGAACCTCTTGAGCAAGCCCTCCCACCACTAAGAAGAAGGCGTAGTATGACAAGCTCGTTGGAAAGCAGCCGCATAAGCCGTGGTTTGATCAAAAACCGCATCAGGAGCATTGAGTAAAGGAACGGTCGTGAAGGGGTACGCCTACGTATCGGAAAGAGTACGTGGTGATATGCGGGTGCTCCAATCGATAATTCTGCATCTATGTATAACTACGTGTGTAGCTCTGCGCTTTCCGTGT ^e W- D - TTTGTATGAGTAAGATCTTTGGGGAAATATCAATGTTATCGACAACCGTTCTTTCCTGTATATAATAATTGTACTTAATCGGGAAAGAACCGAAGAAAGGAAAGTCTACAAGAAATGCGAGATAATGTTTTAAGAGTATGTTTTGAATNECTNCTTATCGTAGGATGTTAAAGAAGTCAACACCATCGTGACCAATAACTAACCATTAGTGTTCCGAGGACACGAGACTATTGAGTCTTTCTGACCGGACGACC_CCGAACGATTTAAATAAAAGGAGAAGGGATTTCCGGAGAATTGGAGATGAAEVUEASCALALAUATFACCCAGTAGTAAACCAGCAAGGTTCTTTCGACAGAGATAACGGAGCATAAGCGCATAAAAGGGATACGTTGCTATTATATAGCACCAGGTTTGCTCGGTTTCAGAAGGAAATATCTGAAAAGTTTTGACCGTGGACAAAAAATAAGAN DTCU EH MNCGCTGGGATCGATAGTCTACCTAGATGGATGACTAGTAGTTGCAGGTCCGTGTCTGATCTACACGGGAATGCGTGTGGCGACTTCCCTCCTGTGTGGACGGAATGACTGTCATTTGACAAAGACCGATTTGTATACGGTGTAGAMOLMCCGAAGGDN NGTGCATCATCNA TCCGACCGATCCATGGGAACCCGAAGAGTACGAGGTAACCTTTGTCTTTGAGATTCATCCATTGTTCGTCCTGGGCTTGCGAACCCTCCCGATGCTACGTTAAGTAAAATTTAGTCGGTCTTGTGAAATAATTTCTTTCTCTACTCCCACGAGGGTAGGTAGGATTATCTCGGTTTCAAATGTTAAAAATCCCTGAGCTCCATCACTTCACGACAACATCCACCTTCCGGAGAAGTCAAAAGACTATTTTCGGAAGGTAGAAAAACTTAAGTAGATGTCTTUAMD M4TAACTTNAELBATCTCCCTTGCAACCGAGAAACGAGCGTGAACCTCTCATCCAGTGGAATAGCTATTATCCCTTTTTATGACCACAGGAGCCTAGTGTAACAGAACACTGTAATCTGATGAAGTACTAATGTCCTTGATAAAATGCGAGTCACTAAAT AGTGGGACACTTTCGCCATTGATCCTACCAGAAAACGGACACACTCTGAACCTCAATTAAGAGGACATTCTCCAAACAGAAGAAGCAAAACCGAGTATTGAGAATAAATTAGAAGTGTTGTTGTTCTATTGAGAAGTATATATT ^W-ev tcudor EUD -DIpRTESONACTACATAGTACTAGCAGGTCTGCATTAACTGTTAAGGATACTATCCTACAGGCAACTAGAAAGAACAATTTTATCTTCTTCTACAAGTAGGGTAGCTGTCACACGTCTACGTTCCTCTTTGGGGTGTCCAACTTGGAAACTCGTATAGGAAGAGNECANTCCTTTTGAEVUEASCTTTGCTCGTAAGCTAAAGTGGTGCTAAAAGAGAACAAAGACCTTTCCTTTTGTATCCGAGCGCTGCCATCGGTAAAACLGLAUGFACATCGTCCGGCTGAATCAACAAACACCGCGGACAAGTGGATGCCAATAAACTGTAGATCTCCTTGTCTGAACCGAGCN DU EH MNMOLTACATMCAAGCTGDN NTTCTCCTCACGCAGAGTAGCTGAGTTGTAGATCCAAGTAAAGATGTATTGACCCCAATGTGTGTCTGCGTTCGATCCCNA CCTGCATGGGAAATGCAATTTCACGTCACTTAGTAACCTTAGTCCTCTGGGCTAGTAAGCTGCGTCCTGTGGATGCTUGAAMATGGD M4GGACACAGCCGTACGTGTTTATAACTCACACTATTTCTAGGTTAGTCAATAGATATGTTTAACTCCCACCCCATCGNAELBAATCCACAATTGAATCCCGCTCCAAATCAGAACAGACCAAGAGCTGGAAAGCCCGTTAGAATACAGGTAGAAACA^ ^ ^^ - - eanmmemnun oe reero seuencesoe m reerence reerence.n reroes were ane usneaner v.. ane m ouuees were o reraerneo c waurease v un.ro.u ucsvne oreaanraeon recomonneac saeeuences,e w reannoaeenes aneavor seo “orna”. cans c v.. secc anmens anamrovee omare sran an non-sran onesnaons were assne asrevorusormaensccre we.nee n-coen-s corann-snecormca reoanmen. an ocus was aaceoe sne-ce oec usn a moeorm o nor rom sceerore v.. aownor seuencesesnae comneuncona assnm as unroucve or w sne ea rcaennss’. anassreomnanene unroucve orermne ce receor o cesn ceuasrrearnem aesnos wresenne ce wsro nmon c-uusnecrsona an. an conr cas, aoue maor rearranemens, a suseeano exressu e receor aa cans.,ae.seero reecnoemne anuncona or comne -asosreamen onse, res ma reece ear anassmeon uncona conuraonunn on. o a seuence cones exn a aonse mssnenesn se.veroaans,ances oca nnons- arsoouceevcee anerm sneeuernancescsr aon cusers.s suessae an oc acure an accesse cross recomn sae,oseor acve cans ac rea eavso esn an cn. eareer srean. rsecraoonnaa c ausenrss wase oen esea sesueenc see ouenearraecoerne os, ces m anau,r uaomnae,.e s.rons exrorersesssonon osuererenea coemexe a co-exresson oase moce seecon-assocae mo rouo onse anncreasen seecon xroenox,ncave o successu- verarennc.oura.e eeecon o rare,uroucve recomne a cesne asencma, cansese anmasreaeorasu a reerorene seuecnecn o. aowm cusomer ana anaznss reeveaereeraaoo+ +o cwe cs coomnserue an aeroexmae^ - - oe+ceouaoncomareo aroun cesca oser aou w w-e m–ce+..neresn, aou man oese ces were–ven–erocessenre ce maura.onso suowesns sueccesasu successu reco umnenraoonneosve seecon, a ereraoo oese amc anmas, cans oserver .-–.n+e c oes,u+no ces,+cse osserva.on a.nso wuorevoousc s aunes-n se n vnoam ronnana cvorerenaon cuures, wc aruemaonsneneran+ceso ae erenaon socoma omex cass exresson ornecen -acne oaor suc exermena seus.evereess,– +ces ca raconsn resumaecauseeeeer ces aso neosve seecen vro reconze cass res exress uuous cassans, wc cane cou aceveosve seeconrnc aemcs.-recaaens anemreaosr uesnese ex vv ao smearren meacoannsm cuures w eren -ransenc mcroenvronmens.+co- romevers o -reae mce a w ce o-cuure o ces–s / –oae wcac cass exresson sow -eee s–enoc+esrom mce .owever, mauraono– +e n coeosr omaon o ces s.- sen–o / –c coe-sc,u wure a noaencreasen+ +ocucurereos wveen, co-cu cueres w was o wserv-ene +s.es, c-nca.n acaoncs cnon mcauureaoonseveon seeceon a sna seucnceses aus menaceur oaon rerorammesromro- cesenerae ouseemus, seccane- suesnne a conve vrr ears nce,eens on cass moecues. -,enneraeeerro-era ceoso ca,n exn vvorn cco-cueureserernoauceeno+e–+ce ces –, / –,nea-e.a–o / –w,eve-r, co–- / c–u,ur-e w– / –s,en-oca– / e–s raecsun a murne cass moecues- .- en a sncan reucon oese evens resenn ceonss.erns aa cass exressons resrceoroessona anen- auseae mauranon oow a+un caensnne n-orne-anea amem nocn m-cem wc e onnvro oncmceunr ws,ns^ - - s roeceonna sruomrnoe or maanusr,a suocn a ansmere nnoaeso ann oem smeen,o o wcave a secaze a cononamsca mrcceuaarveeroenno ruencoereno auoss sessec am veu erne cmese.uan o maure ces, c sees-, navee cees areannosw, anoro ucnesesroa soeneannesou osnomeeorsn esas. encn cer s oocenearr -aos .ona o uc ason cn en sucoucneenrn e oservencreasen ce numers semmerome eran weer raeranromomeosacr acua creaon o new ce conoes oxn- / -uc an- / -oeraonrere m ever,oo samesrom uanave assoxn reae mce were anaze ee seuencn.o cona essevers o sneserous, cans comuewo mercs: sru,o wn scoe us.zeesmmssoonn cnoncaesonr neoxr,maavzoareon ov across same szes, anowerawower sensvo seuence counsa ereannon conaueos versa sne coneo res, ranesromo, werencaes mnma reuences.e assumounaoan an res sunsnesn mcarexamseumomveeorssaca c coenesroreseen a eua no suore ennsemson cona scores were sm raon was rous, suesnenroucon o new s ra ar acrossoreamen .. eran mere exanson o exsn cones eeen seouencn soaon mc wassoaerom sna-rozen seen sames usn am seuencn waserorme as onerure meanuacuroer’seencsr ruecarroanns.e eae cnea sneuences usee m aveoecnooes accornoe manuacurer’srooco. n rar was seuence aveoecnooes.aarocess ereare ene man wasone usneaveoecnooe nemuexn,rmmn, escre. srorearaorm asrevous rearranoenmssen wror suesnoxn- / -mce, cansene a scarce numer o re ens, we averae coun o unue conoeseneweran ane mceerorreeaeenorreomanasn w occue sow aeew a sn ecxananencr ceaosneesne. num.er c oonras,^ - - r wearranreevmoeunss,n wns uao urneaumee rnea,rraun neomens .-.oeer,eseaa annmmunocomeen m aone, eevaes nave ce couns eversevera,,eu ae se anuemnacsn. anass corroor ce reeroren aeseeveomen o a rumenar, urer cara -reae amc mce e aon o nove conoes, -rze e asence o aomnan en or amreerence.nuce -ecxano’sseroera exoceremse rensurnescae caassu an mau-craomon o ceroenors ereoreoeszeae ecocaenerae ce een s. cans crcuanneoo m eere o neec roenorsa cansoun maure.venae seen oromeo seconarmo oranso mraon an acvaon o cess, es asnenaaorse cermmamrunoca,ona wnere a cr cecsan roerene cass-comeen s, suc asenrc cess, canse ac w roenorsn-reae anmas caneeecene see se e ce aer as o reamen an ours a n. cans exane seens susana we an sze ereasnecon. cans oserve areae conros as we as ancere-masaec oe seoenxns+r / o+m anma-sreae. anma-s reaveouc ero+rme+ow ce csonmer- arneaeoun anncreasen overa+mmune c+e.s an+scaencsc naex reveae a sncannc anmas ..enone+c+eracon -reae anm rease aunance oo sne-osve an cesn oeaesr r uenaevrseaouc-m-reae conros.. ces, nowe aecse senc arcecure an mauraon ommune cecsanresseneronrm we-ne s, au semucencn-r uesane, an amamco caracerzeees o maro uc-reae anmas. e a.,cencemoacoao.co arnermerroes wereesne asescrenan e aan aocroesaes an were-eseneneor emaacaenae. coeec mocne, u-seanrs os srumer w aenre^ - - anaecseenzes wsue-seour.an.e a.no rma ecaae.e mouse seenssue was coece an cononuc,, an .enouen s.ewenossoueonca. re.. wcaasesroze wnerne coueceor eac sore a - °.or mouse seenssue sec nroen an eca onn,e seenssue wasranserreo crosa aaceoass- aono cmun-woeames crorsesr seeaceon ws a -- °.e sces wereranserre an ano-- rmeoxsro meacrae .esne. r maroceure was conuce asescrenanan e a.,cenceemeraureore m,n,ee sneeernm seacesz weer wexe wrece meano an - °or a an roooumr. we sames wueenrcenen soauenonrom. - m°mreeezero roomemeraureor mn,enuence m cne,.ween-n a raosom,. ase·nasenor, sames were rns emeraureor mn.eruencn,e ase·ne wasenorwce suemene w. ween- an. rzaonuer , orma.ene sames werencuae w o mmeas ,. aseme, m onuceose vana comex,. a a concenr ·n, ron--,ooeaoc anrmerroes sa aon o ner oo a °n aume oven waram wran an uenor.e sames were wase w wce an -sa wasn werer rnse once wssoven o ance,or mn a °or eac was.na,e sames e sam roomemeraure. ase,. mes wereenncuae w a aon mxure.ess uer a roomemmer, an. o ase·nasenorn ase sames were waseawucree worreeours w aenne senanncu.aeer weaon r roeacnon c,re amcaon mxure.es ce -amnoa s omerase, , - uer a °-or m,n. menm ° an. o ase·nasenornwce w .ween-norreeeoourers weneenmeo sraran s.oree a sam °es o wveerrne was.e^ - - mxure me ne mxeaac,rec s aacmes we erseerreane w m soumrescarorneaaereu meor ac raonemeraureor oneour anen wase once or mn. oom anenncuae w monomerue e sames were rnse onceerameeeneamnen a °or acrame,. s-acrame,. omerzaon mxure. am r mn.eneuer was asrae, an was aeoe cener oe samem anonummmeersauea ceovesrseovenere-cco-ocoeae monoameruer ecroncroscocences, -.eomerzao ss covers our a roomemeraure n reacon waserormeor one emeenro n anox,en wase wceor mn eac.e sames n e a were °oerse w roenase mxure. mmroenase, useuen,e reeours,en wase reemesor mn eac. narccosaa sames werereae w eosoraon mxure. an wase se,re.e mm n narccosaaseuer a ° overn sronruer seuemne ocs rmno am,r ea mcn e, s.e eacue.nrcnon c-ceenan w a rreoaomnee same w or mn eac,oowe wasn w m reemesor mmeraurewce sames werencuae w a seuencn mxure n eac.ene , reanroe, an econroesn. aseausee,r. a m romemeraureor aeasours.e sames were wase w om uer ormamen uerreemesor mn eac,e wasn anman anmanuerorman.maes were acu nmmersen wasn w ommerson oecve . are usneca conoca mcrosco × z. sann waserormee n voxe sze o nm × nm × nmx × roomemeraure.e snaoreers cce usn n orours aman weree was coece aers cce oman.our cces o mes a roomeerrorme meraure soee oruceonce mnn,e eacen se .asm.es werereae w srnuerree mesor mn eac.o vsua e sames wereen wase w m ree werereae w amnzeo saennasm max muermerane aanm ano ceu soeresmceennaoen,aen s aanmes^ - - mn eacn.e aam roonmo semnaera wuasre co oveercne an,ene wase s wna was remae wreeemeesor weremmersen w. a sames marm mnouorescenean. a oe^erroes^are^enemo roenex roe seuence : ^ - - aroeenemo roenex roe seuence : ^ - - aroeeneamo roenex roe seuence : ^ - - aroeenemo roenex roe seuence : ^ - - aroeenecmo roenex roe seuence : ^ - - aroeeneoxmo roenex roe seuence : ^ - - aroeeneemo roenex roe seuence : ^ - - aroeenemo roenex roe seuence : ^ - - aroeenecmo roenex roe seuence : ^ - - aroeenemo roenex roe seuence : ^ - - aroeenecmo roenex roe seuence : anroeenemo roenex os roe seuence : ^ - - anroeeneemo roenex os roe seuence : ^ - - anroeenemo roenex os roe seuence : ^ - - anroeenemo roenex os roe seuence : ^ - - anroeenecmo roenex os roe seuence : ^ - - anroeenemo roenex os roe seuence : ^ - - anroeeneoxamo roenex os roe seuence : ^ - - anroeenecmo roenex os roe seuence : ^ - - anroeenemo roenex os roe seuence : ^ - - anroeenenmo roenex os roe seuence : ^ - - anroeenecrmo roenex os roe seuence : ^ - - anroeenesmro roenex os roe seuence : ^ - - anroeenemo roenex os roe seuence : ^ - - anroeenesamo roenex os roe seuence : ^ - - anroeenermo roenex os roe seuence : ^ - - anroeenermo roenex os roe seuence : ^ - - anroeenemo roenex os roe seuence : ^ - - anroeenecrmo roenex os roe seuence : cence ma anaa e an aasasu wrease,rorme smaroan an an e a., aceve wue – .re,maeeconvouon was :sv.n, usnensssen aao vrersmo,n w.:cen ancoeumeman,eeerans, can, anarcoeern wereerorme asrevousescrraons.mae resraon, so a eem e. mu n sneneaconm:ae wmrove conraseween ce nuce wasenerae conras usnenveorre eacamen oo s vaewnnma.e an sannmae aer enancn rane usn a manuaaeerannaase creaearrosme s senmenaon moe wasen e moe was aeorec se ecaa.useuen, ssue reonencaon:menaonor eac .^ - - aacan smooosoane oovwe-rr ae suaenace.ea.uanraeen scaeranscronaaerns overessue, waserorme ranuaon.e. a neares neor mes o ces e .e seccow-asser use was aeaerne wme=. wasen oroowrmee on cuseer rensunno swa-ceassoroeruece c ceae-o-rceane marxoen reoneaures, cuserno avo smoon reonaes.-means was useor cua conroe-en causce saa auocorreaon aracs. exressonreose ws werees nsormanaze resa ansca anon e:xresseeweranenes were excue.ene cusern aroac wasen uzeo sc careea ues an sreaen-eavre cceaner aoncenouareso.n.erarcca cusers wereenerou-means cusern oerero na, conann enes, wc wereur cesseene exressonroe acroaes, anenrc ces.eesr caacenor ezxeresnsoono our aneve o cee seecees ceense, ma cres, were removerom suseuen anass.aceve cee ers cuserno esaseve annoaon unerwen aona-means enerae cescr, s.ecca, ces were suveno ecoca casse ascvaeacroa ces , an ces a.acroaes were ces wereerenaeno ces anonocessr,z, weenrc nec cesen unerwen aerve- an-m cear.eve ces an urer renemenn c ns cusern usn aane o marersor eoroo enrcasmsecaon. ermuaon-nase ana ass: neoroosn eacs roacromu was useouanocaze ce e sue secon.or eacar o ce es,e anass cacuaes an cnormcamreeno s wcorae woau reeec exseocwe oen c caencse. osesnevwoes areounn coseroxm o eac ceear wn neo oves comarne oservereuenc o cees roos aans a nu moea assumes a ranomsruon -vaues so.wnen sen cocrarensceo onne eneracmamesn. scoress assesse usnermuaoness ase^ - - senoces, asasenses oer a-cenveaornoeesve wse,r aenesenae anamemsau aren o accurae sue exressonaerns ..esne weu were s ce saesase on ssue comonen oe seennosnc reonsn aa oranzeemo as ceoces anerareroar orme e nave seensoosuc w-means cusern.urermomo sea usn anerorme sun roxmn ss re, cans mae ou ce-ceneraconsase oner ase onue reecuonncsrouncaonsene. se,ncs.-. uanemmune cesn a ca arcecure, cans-semene an mce, cansounaeuresooca.- arc..nuc-reae amc erareroar ce zone surroun ecure an sereaonno a srue e severe reuce ces an oersacroaes, ans was a reeneraon os arcecounre oa c weassrve.n.e a-reaoen o mce c,eo cwuevseerr,s neomonosurae uc-reae amc anmas..uanne cesnese reons sow nn aona ces arearemmaure, w some oemavnror eaese osve+ancans a+esseo nave sne- so c oesse.,.. ..revous wor rve a susanancreasen c cesne maaa seenrom-e as sowna amnsraonncrease numersnee xressnroenors. amnsraoneo a ssemcncreasen oveusaons.s an. acoannas meerceoanresm ooeseze mae o-cosenrvaennncrease an sroaecn,c cnuceseveomen o sromroenors.n aon, cans ose wc acvaon o suesne ..s neerreamen w rv me ena anoce or recomnan roen was aeo recauaeencreasen ne ces cans oserve wu -ream vaccnaon-secc or nave esewo mecansms o re enn ae anmas, cans reasonea ces areuenaomeen s areeenerou com aemroenar. receors,recnemo are cessnvovn cemones aner ces s. as wne seenor eecveneracon w anenresenn seconarmoe oran csemeoene s reeceen.orssarc-uaerenmenoraanwaors v cea mor craorroenco^ - - oousnonann a ceso,n aoowennreemseno a eceenr num enceorsuner a.n r-eso,no anens. cans eves ocr,oena exanneromn mmaure ces exresse ecause ce mauraoneens onneracoone w seens.. ceuar neoroo ommaure ces usnu.o , cans anazee cacuaes an enrcmen scor r eacar o cees,e anass roxm com ea reecsow oen ces owoes areounn cose see areo wa woue exece cance.aaron sues o mouse a snmsaavre c reeveaees ae snrono c asussoceraooneeewr,e aenr ces oe sameenoc cass, suesn wc aearsoe aerv nce reerreo asomoc assocaon, aern erne oranzaon ommunessue. can+s / +ounsncuns co annsse cne asc,r aonss e mxaeonrs ceoesse csomnmoen c wese sucu as o m w-eoxn anmas, c aenm-caes,n merrraocrnons weerreaacremeoe meo ce comaornmocenesnuc-.reae.oxonu- / -emerence o ceuarneraco ons am coens, manurn-re caees a asn wmeas asewceaenns o cservee re- e ., es ansn uncona,o vercans ea. xraece ec.o aca+en ceeraser nave cesenerae- / -reamen are as w an evauaeerun ome seens ooxn anmasreaeor e ce cones,- cona usnree mercs: caacoroucewo enaemen oe, an an -, uon acvaon, a oroeraeoown cansouna co emcoeecnacenromon ceuar cooxc .. uon smuaon w onomcn n vvo-rouce cesrouce- an - comex, s .owever, smuaon wese comounsassese e comexo, cans asoesereamen w a anoes, wc enae ouna resuen- an -roucon as we.ven w s assa, cans cessoaeer coems wrom-e-r meacee anm.asro-uce smarevesooserouce e .urermore, -erve ces αmonsrae en wae-meen, wevecs o wasruoreeraon acvn resonseo acvaon . rncrease we aon o nm- .^ - - moce roeac assoenss ,- wrvcens c woeox ucse,o assescsans ceuerorme a one-se mxe conex o aoenec re- / -aruncon,arcuarKbne we m sonses ..oxnKdmce exresse cass- aee, rnce ecc ae,o wreaccvac. cesc,a anrse c oon-cueur-e soreene acnacaroun.s msmac wn eser –-aee -erve ces an roxuorescen succnm ow come sr ..erours s oe cnoo-ccueusrer,omcan mscoeu ann a senn anacanzeo csse os rea enocesne seus wo -erve an w-e eecor ces cevse, woce non-cans co wnerreo as.eos wraacs accomaneuon a snscanroeraon o eecor oeer,ese resus sowa-reamennuces.e ac-. ces an sne seens o amc anmas cumuaon o maure comarae ceuaruncons .cocaenerae ces exe anmas, uner reaveosoocaeveoe cesrom w-e moran,secmorunaceeeo aesnseassm oenses oe ce cseo conrueo aavemmune resonses. enerae reamen no uncona reveaea maure ces roeraon. ex unnaura eves o acv or anorma : onaneouse- moe an c mncca an moecuar monorn n- swceer weee werereae w m oruc m encasuae eeve or weesoowe cnca an moecuar monornorransencoomrene o ae ..- cracr .esavs . mce xermena enounoreacnsvee o reco wnaszn reace-n anncmuaes w asosoove councrorou. m nwoneenen measuremens orn anma oseeves e sae o reamen wasnvesae.seveonucosura. as an no aece we o ae anm cans conrmea reamen course o as o-w as reaveoreamen wucs overe sae o m eeacareeamnensssr.eame-n re.avecoan ssseemn acssesroseenee revaerve.^ - - orncaensa ocs serevaeos nso snncacoarns can aensnvreurunncno mncaeramreers suc as,,, comareoose recevn recomnanroens or eae w m-s an eevaonnrcere a sane conro.owever, cans saw s noe eves, wc councaeeresence orreaown o s,u m aoncrease serum coesero or eves ..urermore, or a moer naoenncruecaese a snn-caenvens, wammca aorn ress wonser comareoe conrorou, exce ormuaons ..onverse evousrecnca evauaons o- exe sncan eevaonsn-,, mcereae w recomnan - an- eueson rase esenn-s,s w-e, aenr-reaemves.. sease vaeeneraon o auoreacve eneaso auommune rouerocess o neave s ces, wc areca emnaenemus rven non-o eecon.o answers, cansrsurneoe ce-oe eseaec mouse moeo assess reamen aecse susce cono aees .n mce, srou on auoreacve ckeds,e man os mmeoo- o wcseecaeneoosream vaee- eramer sann mo oe.ene aresoor exacerae , cans use mceenec meucoos eex,rescso osunra, aen auo-reacve ceeves,.. mer a seru ce es waeresnaseneeves owce weeorve wees ..narae, cans monreae wuc or oo an urneucoseesn. cans asoeror oree onse o va oo oese anmasouan ere me weeow comerromerera sa reconzee uenc o crcuan auoreacve ces carrne no sncanerencen-oo mumcoosoeeev :. cansoun eweenermae mcereae w oreus.,o oraeesncence. conras, a . mceev csrououe-mon oservaonero. anass reveaeeresence oeoe wees o ae ..ow comer o ae, w arore --seccsn aese anmas as ear as wees n . mcssvencreaseo aou --secc cescomareo near correan we eem.eroewnceeve or, censcae eev rsenn vara –e ameornencennvua-s o-vserecmce –^ - - c seusewe.en- anuc-reae mce no reac sasca sncance a anon oenese anmaso,uoom. s comrocmanses w.ere enccoanurae e resusne mce, cenraoerance aecse manenance o ne sereore esase a secon moeoes c-m mce, wcossaesvse a sereacnsoenn aca cnosns aruecrmane ernvcoesee an exerne.ssoncans use ovaumn, aon w eemensrome-Kbane-Dbaees, o ccen ccenea acnromoer ane comeaovrus unere reuaon o a coeneu:raon e cnosmureesx r,o reucson an mmeae-ear enancer.s za wesreaermne exresson oeb--breconzae - s.neec-m- mces,, anse con --- comex, eareveomena sae,n conrasoen suve exresserom an vaccnaon exermens.snerna exressonn srouuecces exernaoe as orearnosrmm’es mneceanresmvous cenraoerance,eano asooca asence o ces ormmu s o . cansreaeese mce wwooses o eeru noounsa reconze wee over ave-weeero.o assess c or s, amnserewce uze eramer san weer cenraoerance wassrue, cans auoreacve anoe noeec auoreacves an an an- an- or eec an ces secsc..oown ave-wee+reamen, cans+noneereraoo ooerse mce.emoersan-,n ces or-n ces sowe near-zeroeves o c comareo w-be mce,c-m mcereamen,ncan a connuouse nesanvnoe --eerououe cans caeneese anmas we seecon aanseses.-.n aon, .ns caene exerm an exoenous vaccnewe sron auvan u neer noru en, w-e mceeveoe rous an- serumeves, ..na,creacec-m anmas sowe an sncan ano resonsemmunocomeen,u ansranserreenecaaee .ro- cesno ssemca crc ae . anmasoeer unersaneae ommaure,u eranserreuan cesneresence o amuss.-. canseece cans s ceesecneemmmauusre as ear. as ceosurns aeer.vm.unse oc roencen. anm.as.eroweavesr,,^ - - meau sreen o recens on conane sne-osve . ces, suesnaurer .aon. an neave seecon e recen’smus cannrnce occurns conex anensn aoee aer, cans resus suesa we enancesmmun aansoren or's sa nmas,oes nonerere w se-oerance.s unerscoreseoena assocae we a recocmaonna.n coonnaer,eam aveonseoena severe averse eecs an coss *s* or ceuar rerorammn aroaces. aro * comosons, aus mocaons an varaons oeescre meos,armaceuca rome scoen ans s ore oscoesures we aarenoose sene ar wouearn connecon w secc emomencso,sure. ou escosureaseenescren mocaons anaescosure as cam we seou un neorsooeas caae ourer emomens.nee, varous mocaons oeescre moe usnumeo suc secc a are ovousoose sene ar areneneoe wnor cear srcn ouescosure s acaonsneneo cover an varaons, uses, or aaaoe oescosure. oown,nenera,ernces oescosure anncun suconse oaescosure resenscosure come wnnown cusomarracce wne aro ruresrome erans an mae aeoe essenaeauresereneore seor. wcescosure^

Claims

- - as cames: . como nuceas ce oonne c oorm er mr enors aen oo: n onuc ceeoes encon one or more acvanroensa aressue a weerveer c veecroe ceonnorsureroe eron eneor av c eee .rs,e an one or moreonuceoeso a . oec co smnoasnon oa cwaam or, o w aere cne reec oeneo orr more ac svnaannraoewnas.s an aons o a . e co,mos,ona oe ca,ma, wee,re orn a ceom aonnaso oneereoo.c snanawa comrses . seo ccoommoason o co cmamex, weren cases a oorns o caess sanna.nawas a maor . e c-om, oors aoonm ooo camere,o w.erene cassan comrses -, -, . e, com-os,o onr o a coammoo, weerreeon.e cass an comrses -, - .oencuocmeoson o cam,urer comrsn one or more cones, or one or more^oes encon sa cones.. e comano,son o cam, werene one or more cones comrse-, ,^. e comoso- n,o- ca,m- ,,weren, or a comnaonereo.ranscronacor . e one or more conesnuce exresson oe^- - . come cromse oonse oon o an one o camso, werene one or moreonuceoes cones oner o mr moroerea msm mosec encone one or more acvanroens anor anor cones or a comnaonerueoes. encone one or more acvanroens . moe cocmaoonssona on ccaremase m, were sne one or more ms comrse one or more ransaon ecenc. a, reucemmunoenc, anormrove . ane e cxoomsomose,o an m oc croavmesc,e w,e are vnrae veecovre,r vece comrses a nanoarce, onuceoe-ase nanosrucure, or an exracan enneere reroeemen vecor, a^euar conracenecon ssem.. aeeno covmrao,s aeonno- oass coacmae,, o wreerreens sme verxa v vreaco vrec coomr.rses a rerovra,envra, . em cuosm, oro as coomn on caaomn,er weoe.renearessuesever, seen, smanesne, . meoeovrernnu,con aa creersosueen worereerenaon comrsn: moreonuceoes encon one or more a ccevaronenorerenaon occurs, one or o ceroenor ces. roensanuceerenaon . ee o mnee oro m oore caomnuc, weoereesn aree oenev oerre moroe enoonueceao ceess arneoermaurae suca werene acvanroens ares essue, an . e meo o c ae on a surace oe enoea ces. mus, or a comamnaon orer,e wo.erenearessuesever, seen, smanesne,^- - .neuc meeoere on aanon on oe o c ceamrsoenoors,o woeureenose ovnee or more ce acs.vanroens . ane a moenso o o a anoc on se ona cnamsawao or, o w aere cnee re ocnee oorr more ac svnaannraoewnas.s . e m,eo o,a caem,,a weere,n or ae c aomonnsa ooneereooc. snanawa comrses . seo mcoemoa o ca cmom,ex weren ceas aso onrs o ceass sanna.nawas a maor . e m-e, oor a oom coaome,re wo.erene cassan comrses -, -, . e m-e,o or o a coammoo, wereeroe.ne cass an comrses -, -, . come mrese oone o or a mnore oneas om camss encoon, weerene one or moreonuceoes more m moecues encone one or mo one or more acvanroens one or ereo. re acvanroens or a comnaon . moe mceaoons oa canmcreas,e w meren sae one, o rre muocerem mmunos comrse one or more ransaon ecenc. enc, anormrove . eev mereeo a o an nan oonea orc cea,m ans exosoome,, w a mercene one or moreonuceoes are reroeemen vecor, aonuceo rovesce, a vra vecor, an enneere necone-ase nanosrucure, or an exraceuar conrace^ssem.^- - . aeeno mverao, a oeno c-aassmocae, w, orereernese sm vraex v vecraor ve ccomor.rses a rerovra,envra, .ceomnees,oorooneanor monoereoocanumcseooes en,urer comrsnevern one or more^con sa cones..aenmeo o cam, werene one or more cones comrse-, ,^.ranesc m,re- o,on o- ac c,oarm-,, w.ere,nor aecoomne onramoonreecreoo.nesnuce exresson oe . eev mereeo w o ane o onnee o or m caormesonouceo, weesre enncoen one oer o mnore cones are co- roens. e or more acvan . seea mraeeo, e o aenre omneo ora ca omrs saoa,, wromerene onee o onre m oro mreoreo cnuocenoes aereevere e one or more acvanroens. s encon . eer meneaoon o o anou onee oos cavemso ce,s wnoer senneeo osnev oer more c ceos.nesnuce . ro meenso,aornuecne cne craonerae acvanroens, or comnaons o acvan aevern one or moraeono annuceoerenesa enocno, sa meo comrsn: acovuaanon oroensanuce ce erenaon on ce onero oren moorre c ceansoae a roensro sme ceecs ene o arv u se aamro on oem o a ce ss snsue ere o v ceonneer rom cees,se exssrueess onnerees ca,nae acvan^- - exressncrean aouaon o ceroenors we same o sne cone ces roenouean cannaee acevrcaennaero oen cse,serenaeromeouaon o ce resueers n s,e anec ceneereonnauconeoores ev eancuoaonnne v cavno, waeer aecnvaenroensa erenae cess a or a ercenae o e ove oeoa ceouaon conssn oe^. em mreusena, ooer a o com ccaems annao,n wceeerreeonro.eenssourse.oneressever, seen, smanesne, . ceom meero. o cam, werene same o sne cone cess seece usnow^^

Images