WO2024007011A1 - Nanoparticles for the treatment of inflammatory diseases - Google Patents

Nanoparticles for the treatment of inflammatory diseases Download PDF

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Publication number
WO2024007011A1
WO2024007011A1 PCT/US2023/069537 US2023069537W WO2024007011A1 WO 2024007011 A1 WO2024007011 A1 WO 2024007011A1 US 2023069537 W US2023069537 W US 2023069537W WO 2024007011 A1 WO2024007011 A1 WO 2024007011A1
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Prior art keywords
emomens
aou
suec
comrsn
nanoarce
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PCT/US2023/069537
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French (fr)
Inventor
Gabriel Morris
Ilya RACHMAN
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Immix Biopharma, Inc
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Publication of WO2024007011A1 publication Critical patent/WO2024007011A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6905—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion
    • A61K47/6907—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a microemulsion, nanoemulsion or micelle
    • A61K47/6909—Micelles formed by phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system

Definitions

  • nammaorseasen a suec a s o aevan one or more smoms o amnsern a co rescose.n some emomens,e meosncue neo a mos coroen a comrsn a nanoarcencun aroc omer n some emomnen ons,e ore moreonasenorsoe suec.
  • curcumno or curc one or morenasenorss seecerom a nanoarce comrseusmno- anao o.rn co sommen eamonomeerenos,.ne n saonmoear emceoams aenasr,ce sze oessa emomens, sn e nomeen a em rmn eonmam meone ese,r.ea nanoarceurerncues aaren moe.n some o emn an acvaemmune ce or ceosu aaons aarneeo a oevaesra ocneve momemcuunee o cveerse.xnre ssosmee uo-.mne snos,earen moes a sne canv anoramen w ano n
  • some emomens ammonsmreanosn, asmnrnaserraoonneas a orman orsrnaraone.rno snea amnsraon.n suecs auman suec.n some emomens, ome emomens,e rom aou mm 2 o aou mm 2 .n soe comosons amnsere aose o amnsere aose orom aou m 2 me emo 2 mens,e comosons conssn on somer eamconmamenmsa,one, onm seoo oor a mncoo oruens ssm m encomms.
  • comrosnmer amnneseorn a como csoreo ann co omner osrn mo are naonoarnacseen comrorssno - coem srusnec. a nnano somarec eemnocumenns a,ero mecosncoueme armnneseron a a comos coon an one or moreonasen re n some emomorsoe suec.
  • curcumn ens e one or morenasenorss seecerom a nanoaroce c oorm currsceusmno- anao o.rn co sommen eamonomeerenos,.ne n saonme emomens,e sze oess oarceas aarce na snomen emmnomameer.
  • curcumno or curcumno ana nasenorss seecerom a naneo oarescse c o or comnaonereo.n some emomens,e sz omrses - .n some emomens,e nanoarceas aarce emomenna s, snomeen a em rmn eonmam meone ese,r.ea nanoarceurerncues aaren moe.n some on an acvaemmune ce or ceosu aaons aarneeo a oevaesra ocneve momemcuunee o cveerse.xnresse emomens,earen moes a sne canv anoramen w a some u-.n some emomens,earen moesne
  • o core an one or moreonasenorssns ascoroc omerne curcumnon o srom cuerc eummonome annas,oe or on ceom orn maoroennearseeo.nse.
  • some emomoenmse e ammonsmreanosn, asmnrnaserraoonneas ora ornraeronea amnsraon.n suecs auman su 2 ec.n some emomens, aem conmsroasoonn.ns s aommen emseorem aenoss,e oe arommn aseorue ao mse omroom aou mm 22 .n some emo 2 mens,e comosons n some em aou mmo aou mm.
  • croncnammaorseas remanncurae anresen es,ncun ,nammaor arrsnammaorseas aeraeuc caene.encnacorsnese rem es are sen eucae.eaoocanammaor cascaes acaernae arnsseenn,n acev cea esvee on aneramem raemorovao oenancn smuus, suc as ceran susannnammaon, a nanoarceaowrme ensceaasseus.aon suroreass acsn recuroren snease- -nnammoraso anner comnaons,aeversese aenso ses oaooca aroacoms raosmco oneanses a oeren roace
  • esnv aenno mneoscso.semoeren use a conceua oose nanoarces an meosancueroa ac mens oenvenon reaeo ereoa areevereo anreeren nnasenors an comnaonsnammaon.esenasenors canna ac enrce ae ses oaooca coasmcnases smuaneous v o mue memrane-assocae anranscronacors c , wcrevens acvaon o mueeownsream eseonasenonorros ann coem mannaeonnasncee oreoe cannanmmao srnaroreaonmseu.cuorn sermsore, smuaneousn mue ce
  • r.nusrc suomunesn eereanoore, aoas,ce,ones, acec ac an coroorm.s s, e.., man oose usene cooaru anenera rea assocaes wnvenonscoseeren.n some em -ever ssems o emomens oe ceae.
  • curcumn can asoeormuae as a mea srucura smsa urseoe cruercnu,m cunr,cu exmn an anao-nuesam armeaoorse e ceocms soumnasr woca ou ceurocumer urcumn anaouesncue,u are nomeo,r-umerone, me n.
  • curcumn,semeoxcurcumn, soum curc curcumn,emeox eruo meane,eraroc umnae,enzomeane, acecurcumn, ,-onecurcumn urcumn,,-s-rox--meoxen-,-eaene- s-rox na,,--seron-,-eaene-,-oneeron curcumn,- en-,,, unecae,r-eaene-,-one-rox na curcumn,,-s eon, n e a., aoenne-,-onecnnam curcumn aneerauo an asoncuesomers e a., see asosa e a., .urcumn anaoues n some em o courcumn, suc ase, an,somers o curcumn.
  • emomens, meos oroucne nanoarcesescreeren are oenonc somnaese emomens,e meoncues mxneervazeoso, oranc soveno snorscurcumnos or oerroocnasenors w an e - ,oouzeenoec mxnure.n some emomens,e meoncues mxn souz 2 e 000 e mxure asenorscurcumnos w an oranc soveno mxures rerae.ner.ae,es socvens evaorae use meos ane care,e encasua ocemcaroeres, suc asarce sze, surace urernorma on ecenc an conenseermne accornouse meos.
  • oarmaceucson caneoun–n warsoczens ee.re a.unrcooreoarnaeourna re oerenacermnacesu encsr aen.
  • eo o us some emonm snoemnee s, em nan eoo memareoncse s, r meeaeoos orea usnn anen nanamomaraocres arseroveeren.n some emomens,e meosncue suressn aaooceasen a suec.n suec w annammaorsease.s useeren, a ammune resonsen ao oneanvovesamae ossuesne aoocammune resonse reers meosncue reevne smomasr
  • wc aremm-umn exames ommune-reae annammaorseases, some o eremaoss, renuem oaro ce meae,ncue,u are nomeo, ssemcuus scerossscer arrs,uvene cronc arrs, sonoarroaes, ssemc ren's snroomerem,a,oacnammaor moaesermaomoss,omoss, ancoen ssemc vascus, sarcooss, auommuneemoc anemammune oaca,romarooxsma nocurnaemoonura, auommuneromocoena rave'ssease,casoencurura,mmune-meaeromocoena,ros ros,aees mmeoou'ss,mrmoune-sm,
  • curcumn e curcumnsr-umerone, mecurcumn,emeox eruo mesaneem,eeroaxcurroccuumrcunm, sno,u,m- cusrcu-mnraoex,--menezomeane, acecurcumn, ,-onecurcumn,,-seron-,-eaene oxen-,-eaene- s-rox na -,-eaene-,-one--r,-oneeron curcumn,- sen-, ox na curcumn or,- n,, unecaeraene-,-one.
  • suesemonsrane sae oe ses werease onusenraeronea versus ora roues o amensesra coomn.ouon aso aweseoseeves anoese woueveoeeaures o cos oreaca no a anmas suo ensu ,en mceerrou were use aeennn oe exermena creomaou snevse wnere a mmcen wsoeuree suaeore exermen.e conro an once aaor sevenas, aer wce cnnrcaae arnonesao oor orcaa r eoueecss o amnsraon were assesse oereamen ormanore.cros ona.e coon an arossesons were coecen uere esooaowono
  • nca snseseca rnacs wneream omaanoen: . o wesrees,wc – soo conssenc, recaeen rurea e a weeurn amnsraon,rce a weaurn .. oroor coo nnesm cue rmn. oson – weeme ,.
  • n cnca sns omrovemen xame was conuoaemroovee sueraarcee one o naneo naanrocaers.cese sna ameove exames, scv aansu- an o sue eecs o anearen moeo sue neas are conuce w onasenors.e resus sowae aon noarces encasuan oese nanoarces aumensero oearen moeoe surace eecs o an ,mrove econ oe coonssuesromenammaor w nanoarces conuae ws sc cvn acaan ssns aun-.
  • vare or aern acaveevsn are o meenr ooneecveeresn o.r asvaonaee usn aesrsaouo oar - s somecec eamo exmceunes o snee,c ancoaer, onrc sueveera onee,a aunroes,e wr, oer s seve oraerseaures, we oers eaurencun one, anoer, or severa oereaures.
  • sowsannae numerca are aroxmaons,e numerca vaues seor ome emomens oe acaon asrecse asra ne secc exames are usua reore n somec ecmae.
  • eren areusrave oerncrsoeos oaee emomens oe acaonscose mocaonsa cane emoe cane wn eem scooem oense o ae acaon.er o exame,u no omaon, aernave conuraons oec eamoon.us, wa acaon cane uzen accorance weeacnseren.ccorn,m emens oe oeresen acaon are nom omens e v eoarecse as sown anescre.
  • sowsannae numerca are aroxmaons,e numerca vaues seor ome emomens oe acaon asrecse asra ne secc exames are usua reore n somec ecmae.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
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Abstract

The present invention relates to nanoparticles containing one or more polykinase inhibitors. Methods of treatment inflammatory diseases and method of alleviating one or more clinical signs or symptoms of inflammatory disease using the nanoparticles are also provided.

Description

- ,,se auneca,on ca, wmscrsorereonc.or.oraroevson raeerencecanosn enerrea.o. m envenonscoseerenenera reaeso nanoarces conann one or somreooms orn casencna sonrss o ann mamemoaosr o ussenases.e sameorea or aevae on or more se aooca overacvenammaonseassor man acue an cronc connaesese..,nammaoroweseases suc as ucerave cos,ron’ssease, ec. ,cve,ssuezesmeasese..,uus, reumao arrs, ec. an neuroocseasese..,nammaons anoewrn’s, rsuancnoroonr’ssease, ec..n aon,erssen cronc o overacveaoocnammaon caneeev uesoemoenre o cancer.us, eecvereamen rvenseases a a aroa rane onammaon- an unueuarrren ens a can nrcoe earc. nesamomreaaomren cascaaveeocnu osere ornoeanren ane snuec susce es aroac, weroucnmoranmro ressem.s ,-e vemensnaen care suc as an-, an-- are neeeraueeso, aas noe rercsueneaen o an non cruersaovne onuc oorm reesa ansn aaeonnas.reamen oons a romcoomeens oeneenvceononscoseomeerern rneaeeoo a nanoarceancues eanoamne core an one or m searo-osa- an manuac oreonasenors an meos o usn curcumnonu o sr ron am ceur ee cm sa umome nom.e annsa,oe o orn ae co omr mnoareonoerneaose.norss seecerom a -aren mone someas em aom aenns,eo n aanoeaasr ocnee muroeecruenc ouveeresx areasrseen o moe.emmune ce n an acvae w an. snome eomou-m.enns, someear emeon mmoenes,se a sanreen ca mnov anoramen roc omerne nanoa esneoe n some emomens, mercoe. nammaorseasen a suec a s o aevan one or more smoms o amnsern a co rescose.n some emomens,e meosncue neo a mos coroen a comrsn a nanoarcencun aroc omer n some emomnen ons,e ore moreonasenorsoe suec. curcumno or curc one or morenasenorss seecerom a nanoarce comrseusmno- anao o.rn co sommen eamonomeerenos,.ne n saonmoear emceoams aenasr,ce sze oessa emomens, sn e nomeen a em rmn eonmam meone ese,r.ea nanoarceurerncues aaren moe.n some o emn an acvaemmune ce or ceosu aaons aarneeo a oevaesra ocneve momemcuunee o cveerse.xnre ssosmee uo-.mne snos,earen moes a sne canv anoramen w ano nm seo emme eomens,earen moesneoeroc omer. some emomens, ammonsmreanosn, asmnrnaserraoonneas a orman orsrnaraone.rno snea amnsraon.n suecs auman suec.n some emomens, ome emomens,e rom aou mm2o aou mm2.n soe comosons amnsere aose o amnsere aose orom aou m2 me emo2mens,e comosons conssn on somer eamconmamenmsa,one, onm seoo oor a mncoo oruens ssm m encomms. are seeceromerou aomnaan,arrea, urencoave aow , recaeen, we oss, ane smomae, a enm manur e movemen,ecanconnence,ever, n on.n some emomens,e one or more smomss manuron. no sommeen ems,e one or more smoms weoss. aresco omens, meos orean a suec w annammaorsease arosec. comrosnmer amnneseorn a como csoreo ann co omner osrn mo are naonoarnacseen comrorssno - coem srusnec. a nnano somarec eemnocumenns a,ero mecosncoueme armnneseron a a comos coon an one or moreonasen re n some emomorsoe suec. curcumn ens,e one or morenasenorss seecerom a nanoaroce c oorm currsceusmno- anao o.rn co sommen eamonomeerenos,.ne n saonme emomens,e sze oess oarceas aarce na snomen emmnomameer. emo ens,e nanoarceurerncues aaren moe.n some on an acmevnase,memarunee cne m oor ceeaosu aaons aarneeo a oevaesr one moecue overexresse emomens,earen moes a sne acvemmune ces.n some u-.n some emomens,earen m coanv anoramen w ano n some emomens, amnsraoenss orneoeroc omer. some emomens, amnsr a ornraeronea amnsraon.n suecs auman suec.na soomnes emnraoermeonnesa, aem conmsroasoonn.ns s aommen emseomens,e rom aou mm2o aou mm2.n some emomens,ere aose o amnsere ao 2 2 comosons n sse orom aou mmo aou mm. a suec wo amnen emamommaoenrs, mseeasoe asr oe suscorseess.nn a soameo eocammune resonsenncue amnsern a comoson comrsn a momens,e meos omerneo a core an one or mor neanoarcencun aroc n some emomens,e one or moreonasenorsoe suec. curcumno or curcumno ana nasenorss seecerom a naneo oarescse c o or comnaonereo.n some emomens,e sz omrses - .n some emomens,e nanoarceas aarce emomenna s, snomeen a em rmn eonmam meone ese,r.ea nanoarceurerncues aaren moe.n some on an acvaemmune ce or ceosu aaons aarneeo a oevaesra ocneve momemcuunee o cveerse.xnresse emomens,earen moes a sne canv anoramen w a some u-.n some emomens,earen moesneoeroc onmero. - some emonm soenmse, e ammonsmreanosn, asmnrnaserraoonneas a orman orsnraeronea amnsraon.n suecs auman suec.n some e raon.n some emomens,e rom aou mm2o ao mom2ens,e comosons amnsere aose o amnsere aose o u mm2.n some emo2mens,e comosons n some emoromm aenosu, a na mnomarcoe a cooumr mm. o core an one or moreonasenorssns ascoroc omerne curcumnon o srom cuerc eummonome annas,oe or on ceom orn maoroennearseeo.nse. norss seecerom a nanoarceurer comrses aaren moe c some emomens,e ramen w anou-.n some emoommenrssn a sne canv ano eroc omer.n some emomens,e, naenoaraen moesneo .n some emomens,e nanoarcesessan rce comrses - n some emomens,e nanoarcesscosenmernenameer.reamen onammaorsease.n some emomen areor usene areor usen suressn aaoo s,e nanoarcesscoseeren smoms or cnca s cammune resonsen a suecavn or exn sc ns onammaorsease.n some emomens,e nanoarcesnamosmeaorerense aarsee.onr so umsee enm aoevmaenns, onee na onro maorrece ssmoms or cnca sns o aevanwo or more smoms or cn scoseeren areor usen emomens,e nanoarce ca sns onammaorsease.n some smoms or c sscoseeren areor usen aevanree or more n somneca em sonsm oenns,a umsem oaore nasnease. o a mecamenoree oarcesscoseerenore manuacure n some emomraeeucreamen onammaorseasesscose. nanoar ns,e usencues amnsern a comoson comrsn a onasceenncuorn aroc omerneo a core an one or more curcumnon o srom cues rc eo ummoe s nomue anec nas,. oe or on ceom orn maoroenneasenorss seecerom a nanoarce comrses - .n some e reo.n some emomens,e sze oessannmnameer. momens,e nanoarceas aarce - emomenns, someea ermeonm meones,ea nsa anoar acenureor anceuases o aaren moe.n some on an acvaemmune ce or ne moecue overexresse emo ceouaonsaree overacvemmune ces.n some u-.mne snos,earen moes a sne canv anoramen w ano nm se emomens,earen moesneoeroc omer. some emomoenmse, e ammonsmreanosn, asmnrnaserraoonneas ora ornraeronea amnsraon.n suecs auman su2ec.n some emomens, aem conmsroasoonn.ns s aommen emseorem aenoss,e oe arommn aseorue ao mse omroom aou mm22.n some emo2mens,e comosons n some em aou mmo aou mm. conssn o raconmamenmsa,one, on seoo or mncoorens ssmencom,s re acrea seeeceeromerou aomnaan,arrea, urencoave aowe mo n, we oss, anema, an manur vemen,ecanconnence,ever, n some emomens,one. onne so omre m eomre sommeonmss, wee one oorss m.ore smomss manuron. comnaon asur uesesn a s socmeem emacoemecnns o a naenonvaerncoen enecsasuanonasenor ures a scemacecn aaree nanoarcrcee eeren. nors as usen some emomens oenv ncasuanonase exran soumure suase aarrareamuesnrann sueen ec reo sun rc. eaoenn w we aoossnarsoeucne escreeren. or as cue an croncnammaorseas : remanncurae anresen es,ncun ,nammaor arrsnammaorseas aeraeuc caene.encnacorsnese rem es are sen eucae.eaoocanammaor cascaes acaernae arnsseenn,n acev cea esvee on aneramem raemorovao oenancn smuus, suc as ceran susannnammaon, a nanoarceaowrme ensceaasseus.aon suroreass acsn recuroren snease- -nnammoraso anner comnaons,aeversese aenso ses oaooca aroacoms raosmco oneanses a oeren roace. esnv aenno mneoscso.semoeren use a conceua oose nanoarces an meosancueroa ac mens oenvenon reaeo ereoa areevereo anreeren nnasenors an comnaonsnammaon.esenasenors canna ac enrce ae ses oaooca coasmcnases smuaneous v o mue memrane-assocae anranscronacors c , wcrevens acvaon o mueeownsream eseonasenonorros ann coem mannaeonnasncee oreoe cannanmmao srnaroreaonmseu.cuorn sermsore, smuaneousn mue ceouaonsa mae uenamessue mcro ems e overacvemmune ces as we as oerssue-re envronmen enoea ces, neurons an oers. sen ces, suc asroass, o e nanoarces an meosscoseeren cannerru an suresse esmv reeraeceororwoa crurroenosre oa smeen-ssu.sanenammaonarve manseases an mae anoarc osomesnes a sonmceu eem ano amueeonuss, come naarnmoeanr ecnecsos oee anveeanso onnescoseaeerren are sancue arocearou aresersen waer,e sonaneous.en aer memranes reerreo asameae.eameae are como orm o moecues wer non-oarrooc sur se owo monoaer sees roc suracesacne aueous me acesacn eac oer aneroar scoseerenave an avera um.n some emomens,eosomes emomens,eosomesseameerrom aou nmo aou nm.n some ,,,,,,,cos,eerenave an averaeameer o aroxmae, nm.n some emomens,eosome,ss,cose,e,r,,,,,, or an aou enave an averaeameer oess mceesan n snom cm. uee em aomens,e nanoarces oenvenonscoseeren areneror comarmen.mencomers w aroc exeror an arooc envronmen,e son ese am comers are exoseo an aueous roocoronsacanneousen asesremor ceoren oo sne neanaoearr ccome.nex seosm we emoerm neonn-s,oaer - m emceoesmenscs,osee mecreenave an averaeameerrom aou nmo aou nm.n some n some emomens,ese msccoeseesersecnoseave an averaeameer oessan aou nm. aou nm. erenave an averaeameer oessan s uaens somnceu eme,oum aernes n,oem naneoarocesscoseerenncue a moecue. va ,as, waxes, seros, coesero,a-soue anomncns, mons,oercevrazees, cse,r anes,eoseo.ns s, snos,cos, caonc or scoseerenn ome emomens,e nanoarces osacu aacecuoes a ,oos ossonacu.ee,auno araem nnoeme,o,ososaacceorne , osaserne , anosanoso ,mrso osao cone, amo,seaorsoaos ca cone ,oeoosa cone , searoosa ceroone ,o,eomrso osa cero , osa cero ,mrso oossaa sercenreo ,amo osa serne ,oeoosa serne ,amo,ossearo serne , oeo osa ea a amooeoosa noamne , anoeo-ocsoane ,amooeo-osaeanoamne car eanoamne--maemome-ccoexane-- morxsoaeosoea-ma, amo osa eanoamne , --mono noamne ,searo-osa-eanoamne , osameea , --me , --rans ,-searo--oeo- rans , anoamne , ,-eao-sn-cero--ooeanoamn suc as on e n same ca ermoomne.ns,e nanoarcesscoseerenncueervaze s, , coese s. ae sncue,or exame,u nomeo, - e ar.n some eemroo-mens,,e nan-ooarcecseros,c or oerervaveseneranownn omerneo core.n some e oseerenncuerocncue - . momens,e nanoarcesscoseeren - nasen roocn soor nms asee enmoomrse.nns, somee n eamnooarmceenss,sceoseroereoncncue one or more curcumno orervaveereo.urcumnos areoe nasenors a curcumn,emeoxcurcumn, ansemeoxc nocmens anncue or snec. urcumn.e curcumno cane naura rox--mse usoexeerenn curcumns asonown aseruomeane or,-,-s- erverom a naura sourc-e,,-eeeraenennae-,er,-ounrceu.mna soonmae e.m, wocmesn as m,e cmurceurmns neraceaeam.n some emomens,eroocnasenors a sn oe anao o cur ecnsouenuc wrucm auemn. r.nusrc suomunesn eereanoore, aoas,ce,ones, acec ac an coroorm.s s, e.., man oose usene cooaru anenera rea assocaes wnvenonscoseeren.n some em -ever ssems o emomens oe ceae. omens, curcumn can asoeormuae as a mea srucura smsa urseoe cruercnu,m cunr,cu exmn an anao-nuesam armeaoorse e ceocms soumnasr woca ou ceurocumer urcumn anaouesncue,u are nomeo,r-umerone, me n. curcumn,semeoxcurcumn, soum curc curcumn,emeox eruo meane,eraroc umnae,enzomeane, acecurcumn, ,-onecurcumn urcumn,,-s-rox--meoxen-,-eaene- s-rox na,,--seron-,-eaene-,-oneeron curcumn,- en-,,, unecae,r-eaene-,-one-rox na curcumn,,-s eon, n e a., aoenne-,-onecnnam curcumn aneerauo an asoncuesomers e a., see asosa e a., .urcumn anaoues n some em o courcumn, suc ase, an,somers o curcumn. smaro c mens, curcumn meaoes wcave an-nammaor eecserarocurucurcmumnn an areex uase.rocunrocwumnn c,u arcnumn mreoaeruoce ascn.cnu seomeucorones o curcumn anaoues or meaoes areormuae as me emomens, ceaes.er aroraeervaves o curcu a ceaes, eseca coer meaoes aroraeor use mn, curcumn anaoues an curcumn aareno one o sne ar.n emomens oenvenonscoseeren we - comounsns scomosee emno.m.enase,neo.,ro,oc, wnacsesnereornscoror,ae a rene oerns enre rence erennn. as some emomens,e nanoarcesscoseerenncue a comnaon o n seomnors. n acv o meu emoe mmeemnsr,anee-assnoacsaeen ano cr oor caosmmcnanoanses o smnuasenors some emomens,enasenors or comnao aneous.n revenn acvaon oeownsr n onasenors are caae o enammaorroeome.n someaem emranoscrmenons,aceorso conrnoasenne moarsne annance o comnaonsn snaransucon ssemesn s.muaneousn er a mae u annamessue mcroenvronm mue ceouaons aren m moe.nnoe so smoemese em emoommenens,s,eea nraenoarcesscoseerenncue aaren overexressec ounm ac-vaemm n moeas a ano moecues as ca une ces aner aaessue ceuar comonens suc anronecnr.onen some emomen, nase-e , v anoramen w anou-.n sos,earen moes a sne cansneoeomer oeervaze ne namneo eamrcoe.mens,earen moe vanaes ssem, sucn a ssome sm emao szemenesss, owannoescocemcaroeres oeever neave surace care, ano nmameerueoe omeren, eren are e r suracearen moe,enasenorsscose m cen evereo, an seecveoca enrcen, auommune neucrroonensv anronomre onser caencuese.euesoces,ssue macroaes,roass, enoea ces, comensaoursro- eroa acnnasenorsnerere w mue smuaneo nammaor snaransuconawasn mue ce es ra –onoacn,ee meeanac c comensaor escae. comnaonsne cncser aeneo usnonasenors aner manerenssues.n aon,o meanna ooxecse su assaencens are arrooao ranc,e o-sneanssesvne - ano o evxerrceommee ceseem ccaaen reaecs,vee, wnvecnorms oseernveonavaonascos aeneraermnacooc use. ese susancesn a nanoarceareerena accumuae encasuae ra cearsrome ssemc crcuaon.s overc s a ses onammaon an an enaese use oese susances a omese concern o ssemcoxc emomens,e an-u an snravenousevere aens.n aon,n somearen oe acvae auomoramen one surace oe nanoarceacaes nown marer o acva mune cesrvnenammaorrocess snceus a ea. u :e- c,e ws.cursenrconroorrmaaeon c raenereencoeunnns enacrenreer een a..e eo o mna somnee nanoarce rove. emomens, meos oroucne nanoarcesescreeren are oenonc somnaese emomens,e meoncues mxneervazeoso, oranc soveno snorscurcumnos or oerroocnasenors w an e - ,oouzeenoec mxnure.n some emomens,e meoncues mxn souz2e000e mxure asenorscurcumnos w an oranc soveno mxures rerae.ner.ae,es socvens evaorae use meos ane care,e encasua ocemcaroeres, suc asarce sze, surace urernorma on ecenc an conenseermne accornouse meos. oarmaceucson caneoun–n, warsoczens ee.re a.unrcooreoarnaeourna re oerenacermnacesu encsr aen. eo o us some emonm snoemnee s, em nan eoo memareoncse s, r meeaeoos orea usnn anen nanamomaraocres arseroveeren.n some emomens,e meosncue suressn aaooceasen a suec.n suec w annammaorsease.s useeren, a ammune resonsen ao oneanvovesamae ossuesne aoocammune resonse reers meosncue reevne smomasronesnarac.n some emomens,e emomens,e meosncuemrs onammaorseasen a suec.n somereae we nanoarcess ovn cnca sns onammaorseasen suecs sease,ncue,u are coseeren.nca sns or smoms onammaor een, weoss, a nomeo,racnammaon, soonconssenc, reca owe movemen,ecancoomnnnaencea,n,evear,rr aneeamsao,m anem measn wurono.on, so umree enmcoomaevnes a, - ese masee.on ssomnceu emeommroevnems,ene o me oneo osr mncorue cemncarov semnesn or o smwo oorm mso ore cnnammaor or smoms onammaorsease.mrovemen oree or more cncaca sns smoms onammaorsease. sns orreamen onn soammem eamoromseeanses.,ne som naeno emarocmesenscoseeren areor usene areor usen suressn aaoocammune rs,e nanoarcesscoseeren smoms or cnca sns onammaorseasee.snonsen a suecavn or exn scoseeren areor usen aevan one o some emomens,e nanoarcesnammaorsease.n some emomens,e nr more smoms or cnca sns o aevanwo or more smoms or cncanoarcesscoseeren areor usen emomens,e nanoarcesscoseerea sns onammaorsease.n some smoms or cnca sns onammaorsean areor usen aevanree or more o a mecamne snomeor emeoemraeneus, ucsere oae nanosaer.cesscoseerenore manuacure on men onammaorseasesscose. wc aremm-umn exames ommune-reae annammaorseases, some o eremaoss, renuem oaro ce meae,ncue,u are nomeo, ssemcuus scerossscer arrs,uvene cronc arrs, sonoarroaes, ssemc ren's snroomerem,a,oacnammaor moaesermaomoss,omoss, ancoen ssemc vascus, sarcooss, auommuneemoc anemammune oaca,romarooxsma nocurnaemoonura, auommuneromocoena rave'ssease,casoencurura,mmune-meaeromocoena,ros ros,aees mmeoou'ss,mrmoune-sm,euaveenemoccros, arocuuonersa ners,emenanseases o renea ceseaseomeruoners, ssems suc as mue sceross,oacemenanonnra anerera nervous snrome, an croncnammaoremenanoneuroaeuroa oruan-arr suc asnecouseaseas,,,, an oer non,-eeaaooroarc vseases auommune cronc acveeas,rmarar crross,ranuomaou ruses, scerosn coans,nammaorowesorer ucerave cos,sroenas, an uen-sensve eneroa, an e'ssease, auommune ormm 'ssease, seasesncunuous snseases, erema muorme an cuonne-meae sn sorass, aercseases suc as asma, aerc rns, aocearcmermas, ersensv an urcara,mmunoocseases oeun suc as eaosns,oooc - asnseoucmaoenas,seasoesanccuunmonraar reercososn, anra-veerrssensvneumons,ransanaon seasesncun vrasease us-os-sease, anee.necous eres, ec.,aceraneconss suc as necon,eas,,,, an, aso canavemmune anor,nunamamnaeocro cnosm,roonoeznosa anneocro enso aona arnascerneeocronsreae accornoe meossc ee n some emomens,oseeren. curcumn, e curcumnsr-umerone, mecurcumn,emeox eruo mesaneem,eeroaxcurroccuumrcunm, sno,u,m- cusrcu-mnraoex,--menezomeane, acecurcumn, ,-onecurcumn,,-seron-,-eaene oxen-,-eaene- s-rox na -,-eaene-,-one--r,-oneeron curcumn,- sen-, ox na curcumn or,- n,, unecaeraene-,-one. comr some emomens,e meosncue amnsraon o a comoson amnssrnaones v naanonraarvecneosus,nscraoseeroneerae,n orao,n aa sue,ecn.ran some emomens, ee.n some emomens,e amnsraon nasa, reca,oca, an n some emomens,e am s vanraeronea or ora amnsraon. n some emomenns,sraeons vanraeronea amnsraon. orom aou. m o ann nasenors a curcumno amnseren aose o we.n some emomenvs,uae’sno weo aou m o annvua’s ose orom aou m o annvasuenors a curcumno amnseren anvua’so we.n some emomaen’ss,oe wneaso aou m o an amnseren aose orom aou m o annvuae’nors a curcumno m o annvua’so we.n some emomenss,oe wneaseno aou curcumno amnseren aose orom aou m o annvua’soors a aou m o annvua’so we. weo orom aoun som me emm2oom aeonus,e mnamse2,nors a curcumno2 amnseren a2ose rom aoun s momem2o aou mm2. orrom aou mmo aou mm, or mesera emomens,eosn remens onceera,wceera,ree as,en, oar esv,erreeouro w sexeso,uorsu.rn so wmeee ems, oorrmomen as,ouerveeamenaesnosaves. - norscuarncoumarnocess w were arno ourcaexa nc so mm vxenne oe - ,oenocnase en evaorae us souzee mxure.e soven was scocemcaroer e meos ane mxure reraen .e an conen wereeermnese, s auccco arsarce sze, surace care,e encasuaon ecenc ourna oarmaceucs anonarmoaceuucsse meose.–.,.arsozen e. a.uroean xe xame rerm,enes s wuere c coonnssuece ooouerse ar ems:caco onroe nanoarce oxame. exran soum suae ane nanoencasane onro accornoxame m amnse uae curcumno comex naancoe enxcaersumaenea currcouum cnoona cnoem-ex ac mcocrre e.n v eoan roxar omaer seeonea o mnecon va oraavae. suesemonsrane sae oe ses werease onusenraeronea versus ora roues o amensesra coomn.ouon aso aweseoseeves anoese woueveoeeaures o cos oreaca no a anmas suo ensu ,en mceerrou were use aeennn oe exermena creomaou snevse wnere a mmcen wsoeuree suaeore exermen.e conro an once aaor sevenas, aer wce cnnrcaae arnonesao oor orcaa r eoueecss o amnsraon were assesse oereamen ormanore.cros ona.e coon an arossesons were coecen uere esooaowono mceaas euvraemuaeon. . nca snseseca rnacs wneream omaanoen: . o wesrees,wc – soo conssenc, recaeen rurea e a weeurn amnsraon,rce a weaurn .. oroor coo nnesm cue rmn. oson – weeme ,. aoo an cnca cemsr, coneronammaorane - o xermens asescrenxxaammee were conucen a-nucecue :so,e w ocesarc.eas caneounnrsz e.a.aureroocos ,nuce a erencororae reerencens enre.re, acue cos was causn reucmen wseraona on, orveas sarn a weannosnaaa os- , recauan cooen ccn scorenn, an cooncnammaon e asreae w a nanoencasua acure seennearc cos.e anmas wereo assevsesmeonr e curcumno comex amnserenraeronea or oramro r.esoeu eoenc o ommesuen coomaoouonsca wasea coumresa ore coosa a os w vee acse c conncraos s.ns o nanoencasesus sownnae anureemonsraea anmasreae we comareouaee con curorcumrounos. comexemonsrae cnca sns omrovemen a - e aneroma ae.o onro onnaosre reamen o
Figure imgf000015_0001
eave reucon o we n= n= n= onasen or asescroses were re oerae-o-severe weossn o or more was oserven o anmas comaeex wroureae sanner,a weroeneuas sow oe anme saasmenevee n oan woeencasousas.e csur rceumresneons - a anmas re vaersvuesmeroveme snanne w ceonroosrsoun n.anoencasuae curcumno comex-reae enzene suxonecrm acens c aosess mcroee.neaxxaamm s caee ne areou cnonuncersnz a e. ,,-rnro- o.., : , wcserencororae reerenceaaureroocos moe, a cronc cos w roceaures, smarou ns enre.ns mce exosnemo reca.ne oe mmanron’s, canenucen ncee cronc coss esase os sensve srans o mcesac.reae w a nanoencasuae curcumanoer co-m weeex osr o a nanoenc eaxsousauree, sne aenmca as are o curcumn amnserenravenouso assessor res nao eaures o cos as we as cnca sns o ouon ommunoaooca comareoa o vece c mrovemen.e eec oese comounss emonsraee rseusosu sonow omaon m ar uno noms.aasoroeaeca weaurese a nanoarces asescreeren comareoe conrorous. n cnca sns omrovemen xame was conuoaemroovee sueraarcee one o naneo naanrocaers.cese sna ameove exames, scv aansu- an o sue eecs o anearen moeo sue neas are conuce w onasenors.e resus sowae aon noarces encasuan oese nanoarces aumensero oearen moeoe surace eecs o an ,mrove econ oe coonssuesromenammaor w nanoarces conuae ws sc cvn acaan ssns aun-. reuces weossn suecsreae carr oue ae varcaouosn m.eo cous anecnuesescre aoverove a numer o waso avana rse,soe unersooa no necessar a oecves or eren.esus,escorr eexam aree a,ceovsee sn aecconranece ar w w an recoarnczuear emomenescre erormen a mannera aceves or omzes o ae meos caneau eren wou necessa ne avanae orrou o avanaes as sueseeren. vare or aern acaveevsn are o meenr ooneecveeresn o.r asvaonaee usn aesrsaouo oar - s somecec eamo exmceunes o snee,c ancoaer, onrc sueveera onee,a aunroes,e wr, oer s seve oraerseaures, we oers eaurencun one, anoer, or severa oereaures. mae aarcuar romereurermore,e se arsan w reconzee aca o varouseaures aove, as wne e ams ooemrennos.wnm euarva,enes voarr eoaucs e seumcen ese,meeanu,reesa aunre o sre sse,s ccusse emoen varous comnaons one o ornar sns aroerorm meoansne a scecosr sance werncesescreeren.mone varous eemens,eaure momenes. we seccancue a s, an emo n oers secca excuenverse an ex oue acaonaseenscosene conex o ceran emomens acaamone esx,en weeo unnerseoo ose sene arae emomens oe emomens anor uses an mo seccca scose emomenso oer aernave n some emomens, ana nuomnse arns ex eruesvsanensuereo. suc as moecuar we, reacon conons, a anes onreens,roeres emomens oescosure areoe u n soor, useoescre an cam ceranerm “aou.”ccorn,n some emnersoo asen moen somensancese wrenescron an anncue comens,e numercaarameers seorne eesreroeres souoe oaams are aroxmaonsa can vareenn uon e numercaarameers so ne aarcuar emomen.n some emomens, s an an ornuar reou cnonsnrueecnnue oe numer o reore sncan ranes anarameers senoreroa scoe os. sowsannae numerca are aroxmaons,e numerca vaues seor ome emomens oe acaon asrecse asra ne secc exames are usua reore n somec ecmae. ne con omens,eerms “a” an “an” an “e” an smar reerences use conex o ceexra on cescrn aarcuar emomen oe acaonesecane o ranes o ams are consrueo coveroe snuar aneura.e recaonnvuao vaueserens mereneneo serve as a soran meo o reerrn eacnvu eac searae vauean wne rane.ness oerwsencaeeren, eren. mea voasuesncororaenoe seccaon as werenvua recencaeer escreeren caneerormen an suae orer uness oerwse or exemareann oru oaeerwors eex cameare, c “osnucra asc”erov coene wx. rees uesec oo a cner aann e am eoxammeness, - eerensnene mereoeerumnaee acaon anoes noose amaon on cons scrouee a ose acaon oerwse came.oanuaene seccaon soue anracaon an non-came eemen essenaoeracce oe acaon. sne ar uonn rs onreerre emomens wecome aarenoose o ornar can emo suc varaeaoneoreonescron.s conemaea se arsans seccaescreens as arorae, ane acaon caneracce oerwsean mocaons an euvareenn.ccorn, man emomens os acaonncue a erme acaeaw.s ooreoeve suec maer recene cams aeneereo as aosse varaonsereos r, an comnaon oe aove-escre eemensn eren or oerwse cear c encomasse e acaon uness oerwsencae maera, suc asa aerncs,es,aeo onnr o aac s, sece caocnas c,on onuex. s,cuaocnaso ons,aoecnum aens,caons, an oer e, reerenceeren areerencororaeeren s reeren ns, anore uroses, excen anrosecuonesor assocae w scener enreor anconssen w orn conc weresenocumen, or aname, an o sameas mn eec asoeroaes scoe oe cams now oraer as oso samea maave a ocumen. wa o exame, soueree annconssenc ocra ce weresen escron,enon, anore use o aerm assocae w an oenonceweene ana assocae weresenocumen,eescron,enocororae maeraermnereseno n, anore use oe n cosn,cumseno sea unereva. eren areusrave oerncrsoeos oaee emomens oe acaonscose mocaonsa cane emoe cane wn eem scooem oense o ae acaon.er o exame,u no omaon, aernave conuraons oec eamoon.us, wa acaon cane uzen accorance weeacnseren.ccorn,m emens oe oeresen acaon are nom omens e v eoarecse as sown anescre. carr ou arous meos anecnuesescre aoverove a numer o waso avanaese aescrceao anre. ac coeuvrese,n asccoorea unncee wrsoo anaa nroc nueacres esmaro ame onecescvrese or eerreonrm.eusn, ao mra enxnaemrea, acoseev ses oer onmeze asr on we a rvecanoaneze oraroue o me avoansa caens ae sauueseereenre wn.ou var neeces osar aern acaveevsn are o meenr ooneecveeresn o.r asvaonaee usn aesrsaouo os ar - s somecec eamo exmceunes o snee,c ancoaer, onrc sueveera onee,a aunroes,e wr, oer s seve oraerseaures, we oers eaurencun one, anoer, or severa oereaures. mae aarcuar romereurermore,e se arsan w reconzee aca o varouseaures aove, as wne e ams ooemrennos.wnm euarva,enes voarr eoaucs e seumcen ese,meeanu,reesa aunre o sre sse,s ccusse emoen varous comnaons one o ornar sns aroerorm meoansne a scecosr sance werncesescreeren.mone varous eemens,eaure momenes. we seccancue a s, an emo n oers secca excuenverse an ex oue acaonaseenscosene conex o ceran emomens acaamone esx,en weeo unnerseoo ose sene arae emomens oe emomens anor uses an mo seccca scose emomenso oer aernave n some emomens, ana nuomnse arns ex eruesvsanensuereo. suc as moecuar we, reacon conons, a anes onreens,roeres emomens oescosure areoe u n soor, useoescre an cam ceranerm “aou.”ccorn,n some emnersoo asen moen somensancese wrenescron an anncue comens,e numercaarameers seorne eesreroeres souoe oaams are aroxmaonsa can vareenn uon e numercaarameers so ne aarcuar emomen.n some emomens, s an an ornuar reou cnonsnrueecnnue oe numer o reore sncan ranes anarameers senoreroa scoe os. sowsannae numerca are aroxmaons,e numerca vaues seor ome emomens oe acaon asrecse asra ne secc exames are usua reore n somec ecmae. ne con omens,eerms “a” an “an” an “e” an smar reerences use conex o ceexra on cescrn aarcuar emomen oe acaonesecane o ranes o ams are consrueo coveroe snuar aneura.e recaonnvuao vaueserens mereneneo serve as a soran meo o reerrn eacnvu eac searae vauean wne rane.ness oerwsencaeeren, eren. mea voasuesncororaenoe seccaon as werenvua recencaeer escreeren caneerormen an suae orer uness oerwse or exemareann oru oaeerwors eex cameare, c “osnucra asc”erov coene wx. rees uesec oo a cner aann e am eoxammeness, - eere scnosen oenee a merecaoon oeeerrwusme cnaameee. aocaanoun anoes noose amaon on consrue asncan an non-cam aene seccaon soue araons onre e eemen essenaoeracce oe acaon. sne ar uon reaneerreore emonomesecnrs won.ecsom coen aemareaneoao sse oe o arrnsaanr can emo suc varaons as arorae, ane acaon can s seccaescreeren.ccorn, ma eracce oerwsean mocaons an euvaens n emomens os acaonncue a erme aca oe suec maer recene cams aeneereo as aosse varaonseearweo.sor eenocvoemr, aansse comnae aon ocaeon a uonve-escre eemensn eren or oerwse cear conrace ess oerwsencae maera, suc asa aerncs,es,aeono as, seccaocnas c,on onuex. s,cuaons oaen acaons, an oer e, reerenceeren a caons,ocumens,ns, anore uroses, excen anreroesreecuonncoreoraesorer aesnsocaes w reere snacmener enreor anconssen w orn conc weresenocu e, an o sameas mn eec asoeroaes sco men, or an o samea maave a ocumen. wa o exame, soue oeree caem ans nonwco onrsaseernc asso ocra coen wceweeeresen escron,enon, anore use o aerm assocae w an ne ana assocae weresenocume oencororae maeraermnereseno n,eescron,enon, anore use oe eren aren cusosranv,cum e oseno s eea unrnere crsvaoeo. s oaee e emmoomens oe acaonscose mocaonsa cane emoe cane wnemens oe acaon.er o exame,u no omaon, aer scoe oe acaon.us, wa acaon cane uzen nave conuraons oe emomens oe oeresen acaon are a ncocormancee woaereeaccsen ass sereown.n acncoresncre, e.momens

Claims

- suec c.omrsn me aomn os aerenva an co omneo osr monore co smmoms onammaorseasen a roc omerneo a corersn a nanoarce comrsn a e sue an one or moreonasenorso rom a cu.c. rcumnoe m oer cuorcu om cnoam an,a woe orer cnome onnaeo onr meorenasenorss seece .. ee m meeoo o o c caamm,, w weerreennee n naannooaarrccr eee coo. asm arasresce- . nmnameer sze oessan moe, w. . erenee meo o cam, werene nanoarceurer comrses aaren on an acvaemmuanree cen o mr coeeoaus aaons aarneeo a oeas one moecue overexresse . e meo o cam, werenearveracvemmune ces. anoramen w anou-, werenen moes a sne canv roc o earen moesneoe .. ee m meme eor. o o cam, weren amnsraonsnraeronea amnsraon. aou o cam, werene comosons amnsere aose orom aou. mm2o m2e a moeuo o m camm2., werene como erou conssne m oeor oac cnam2 sons amnsere aose orom .mo aou mm. amm, waoenre, snooen ocnoe or more smoms are seecerom aomnaan,arrea nssenc, recaeen, weoss, anema, an man , urencoave aowe movemen,ecanconnence,ever, . u . e m mr eeon oo. o o creaamn, w aerene one or more smoms weoss. amnsern a c suec w annammaorsease comrsn neo om coosreo ann co omner osr mno are naonoarnacsee cnomrosrsno ae suroecc omernamma.ors meaeseo co om srusnres asnmn asaerono ac caommune resonsen a. suec w an comrsn aroc omer moson comrsn s nanoarcenorsoe suec. neo core an one or moreonase - core an o. nanoarce comrsn aroc omerneo seecer.ne or m om a cueor rc ne uamnoonoarncas oree c on urc cumaomrs. no, an waoere onr coem onnea oorn moerereon,a asne wnorss nanoarceurer comrses aaren moe com erene ramen w anou-, werenearersn a sne canv ano omer, weren nanoarce comrs n moesneoerocsessannmnameer. es - , an werene nanoarce
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