An Open'Label, CommunityaBased,
`IZ'Week Assessment of the Effectiveness
`and Safety of Monotherapy With
`Doxycycline 40 mg (30am Immediate
`Release and 10mg Delaye 'Release Beads)
`
`Guy F.W. MD. F'I‘D
`
`were clear or near clear by week 12, according to
`iGA scores. Furthennore, approximately 76% of
`participants had CEA scores reflecting none or mild
`erythema alter 12 weeks. in the safety population
`of 1195 participants,
`treatment-related AEs were
`reported in 6. 79$ of participants that were mainly
`mild or moderate in severity. Adverse events that
`occurred in more than 196 at the safety popula-
`tion included diarrhea (1.2%), nausea {1.396). and
`headache (1.0%). The incidence of fungal and yeast
`infections was 0.496. The results of the ORCA trial
`support the effectiveness and safety of the 40-mg
`formulation of doxycycllne in patients with papuiov
`pustular rosacea.
`
`Cutis. 2010:86lsuppl 5[I]):7-15.
`
`Posacea is a common inflammatory disorder of
`the skin of middle-aged and older adults. A
`unique 40-mg formulation of doxycyciine (SO-mg
`immediate-release and tO-mg delayed-release
`heads) developed for its anti-inflammatory proper-
`ties is the only US Food and Drug Administration»
`approved oral medication for the disorder: This
`report describes the results of the Oracea' for
`Rosacea: A Community-Based Assessment (090A)
`trial. a phase 4 trial of the 40-mg formulation as
`monotherapy in adults with mild to severe populo-
`pustuiar rosacea. A total of "97 participants were
`enrolled in the ril'ionoti‘ierapjir arm of the t2~week
`open~label study at 271 community-based inves-
`“national sites. The primary outct'ime measure
`was a change in the 5-point investigator global
`assessment (lGA) score from baseline to end point
`(week 12}. Secondary outcome measures included
`change in the 5-point clinician erythema assess-
`ment [CEAJ score from baseline to end point, lGA
`success. and adverse events iAEs}. The mono+
`therapyr per-protocol (PP) population was selected
`a priori as the primary analysis population and satiety
`assessments were performed on all participants
`who received at least 1 dose of the study dmg. in
`the PP population of 826 monotherapy participants
`who compteted the trial. approximately ?596 of
`participants with mild to severe rosacea at baseline
`
`osacea isachmnic demd‘middle-aged
`and older adults that infect: anamimately
`16 million individtala in the United States. a
`prevalence that is awruxiuntdv 4'an greater than
`pamiasis.‘*'Afamilyhistorvnflhediseaseistepatted
`in approximately 30% of patients.“ Rosana is char
`mnmdbydilationofbkmdveeaelsofdnoenual
`facemdismrecommon hpatientswhoexperienoe
`frecnmt flusl'ling or blushing.s The etiology ofmsacn
`umfimn;however.itisaseociaaedwithfacmdtat
`trigger the skin's irmate hmmne response.‘ Rosacea is
`histological]? characterized by inflammation and vas-
`cular changes.1r Patients with mecca have increased
`expmion of epidermal eatl‘lelieidtns.’1 Time peptides
`have been demonsu'atod to have antimicrobial. (he
`Eutectic, and angiagenic activities?” It has been
`enmeshed [Int increased expression of cadlelicidin
`“WHENJTISBUH
`VCLUREBG.W ZOIO I
`wmmiammdmmmum m.ummummmdhm.
`
`mmwmmmm
`hmmnmmmmmmm
`mowebsiarammmmnm.“
`mummmmamumm
`
`
`
`Amneal 1037
`
`Amneal v. Supernus
`|PR2013-00368, 2013-00371 and
`|PR2013-00372
`
`

`

`
`
`and its trvpsinhke proteolytic processing enzyme.
`stratumcmreumtrvptic erirrmelSClTS). arecentral
`elements in the patlwgenosis of the disease. This
`hypothesisis unsalted by imlrlrmohistocl'mical
`evidence ofllincreased cadielr'cidin and SCTE in
`“wellhead-1m. In a more model, subcutane-
`ous iijactltlia d SCTE prurhced armiems changes
`and antimicrobial peptide prtiiles similar to mesoea
`in hutrlalis.‘I
`Doxycyclinehas been shown to have both anti-
`bacterial and anti-inflammatory properties. Pro-
`uiflammatory mediators oscillated by tetracyclines
`include pl'iospholipase Ag. endogenous nitric oxide.
`“/6. and serine protease: such as SCTE'L" In
`addition. the drug damnregulates matrix menllov
`Iiaseactivity, inhibits cherriotaxis and gnnw
`formation. and acts as a scavenger to protect
`cells against reactive oxygen speciesu“I Olacea"
`is a low-dose 40am capsule ofdoxycycline limin-
`hydrate containing 30-rng immediate-release and
`lO-rng delayed-release beads (hereinafter referred to
`as doxycycline lo Incl.“ Its {amulation and phan
`macokineticpmfilearemiiqueindntplmacon-
`centrations do not reach levels prorhcing antibiotic
`activity that would encourage the development of
`resistant organisms.”
`Tetracyclines have been important elements
`olrosaceadierapyformoretliansoirearsfi’nie
`US Food and Drug Administration approved
`the «ll-mg formulation of doxvcycline in m for
`the treatment olinflammatorv papules and pustules
`in adultswith mi‘l'heapproval was basedon
`the results of 2 randomized. multicenter. 16-week.
`placebomnuolled. phase 3 trials of participants
`with m” Although the drug has been avail«
`able for decades and this formulation for almost
`
`Smdwmhvebeennophaseltrialsofitsuse
`as moriodierapy in routine clinical practice.“ This
`reportdescribathephase‘lGaceafor Rosacea:
`A Commuiity-Basecl Amman (CIRCA)
`trial.
`which was designed to evaluate the elloctivaieu
`andsaferyafdoxycyclinewmgina largenmcea
`populationusedaeidiermnotherapvoradd-on
`therapy. This
`report describes
`the doxvcy-
`cline 40 ragmy am if this large community-
`lnsed population.
`
`muons
`
`I
`
`|
`
`IEE'I E
`
`l'
`
`Good Clinical Practice guidelines. US Food and
`Drug Achiinistration Code of Federal Regulations.
`and local regulatory requirements. The protocol
`was approved by a central
`institutional review
`board or
`the investigator's local
`institutional
`review board. All participants were fully informed
`about the studyr and provided written consent prior
`to participation.
`
`MW
`AchltslSyeasandoHerweleeligiHefcrdiesofly
`ifllieyhadadiagnosisofmildtomelepapllopus—
`mlarromeawidruuderatetoseverepenlesional
`erythema. Chlididateswereenclidediftheywere
`[swaplmningmheimiepregnantdmfligdie
`smdy:medauopicalorsystemicacnedrerap7(ie.
`retinoidsjsotretinoinlwilhinlnmrlisofthelnseo
`
`‘lweeksofdielnselirievisinhadlaserorinuense
`pulsedlifiitmtlmntswithinJmonthsoldie
`hueline visit or anticipated this interventionin'ing
`dietimeot'theoial:usedaninvestigationaldrugor
`devicewithinmdaysdbmelilieiusedatrmicalor
`svsterniccortioosteroidwithinlweehor4weeks.
`respectively. cf the baseline visit and during the
`midnhadalmownhypersemilivirymterracyclinex;
`were receiving treatment It: cammitant condi-
`tionsandwerenotoriastabledoseofrnedicaflori
`foratleast3rrionllis:orlia:lanyooridil:iolithatdie
`investigatordeemedmphcetliepaticipantatrisk
`orintelferewididrestildvoutomne.miermnes
`foreitcliniori included kidneydimase. achlorhydria.
`monitestinaltractprohlemsincludrrgsmgervthat
`bypameddiedinderimactivesmemicfimgalmfic
`fioquinalyeastinfectiatooncmrentdiseases or
`a-adrelielgicblodterdierapyinwliichdosingwasnot
`stableorwasanticipatedtodimge.
`Participants were iruuilcted to take I capsule
`ofdoxycyclinelflmgdailyinthemomingcnan
`emptystomachforthedurationoldielZ-weekm‘al.
`Participmtswerecautionednottoalte
`that
`mayinterferewldiahsorptionoi'diesnslymediv
`cation leg. aluminum, calcium. trapezium. iron)
`uptol.5hoursheforeandupto3hclrrsafterthe
`surdv medication. lnwau'ystors evaluated egalitar-
`ticipant’srosaceaseverity and erirdiernaat
`ilie
`andatweelrsl,4.8.and12 (studyend).Severityol
`rosaceawasanessedonaS-pointinvestigatorglobal
`assessment (lGAlscaletTable l}. Attherimeol
`This 12-week, open-label. multicenter. community-
`dielGAassessrnenLdieinves-tisator alsodiaracter-
`based trial evaluated doitycycline 40 mg in par»
`izeddisease-anociatedemhemaonaS-point clini-
`ticipants with mild to severe rosacea (participants
`who otherwise would have been treated with
`cian erythena assessment (CEA) scale (Table 2).
`Safety was assessed by the incidence of adverse
`antibiotic-dose doxycycline) with the drug admin-
`events (Ali's) that were descriptively summarised
`istered as monotherapv. This study was condoned
`in accordance with the Declaration of Helsinki.
`widiincidenceratestabulamdusingtheMedical
`WUJTBCCM
`31111:?
`wows 201i]. lion-1dr.“mum “.m'mmhpinr'hp-Wdhw.
`
`
`
`

`

`Tablet
`
`InvestigatorGlobalAssessmentScale
`
`
`Score
`Milan
`m
`
`
`Older!)
`
`Noaignsorsymptmlspmsem
`
`Cmfleidydeaofhhmutoryiaskms
`
`1mm 1a2pq3des
`
`14mm“
`
`2m
`
`Smepapdesandpusues
`
`3—10pmflesflidpus’ala
`
`ail-manure) mmdmmm ”Aswan-am
`
`4W) Nmmflmmm flmhsmmmmodlfi
`
`Dictionary for Regulatorv Activities“ system organ
`class and preferred tenn.
`
`m2.
`
`Endpoints
`
`TheprirnarywtcomememirewastherhangeianA
`sure from baseline to end point (week 12). Second.
`aryoulcornemeulnss includedchangeinCEAscore
`from baseline to end point. success. and safety. For
`purposesofanalvses,mccessoouldbedefinedasthe
`'on cf treatment
`at end point with
`an IGA scoreofo (clear) or I (near clear}.
`
`CihioianEryihama
`AssessnmrtScalo
`
`
`some
`
`Dinars}
`
`Hrnldl
`
`Definition
`
`Nored'leeeprmfl
`
`56119th
`
`2lmoduuto)
`
`Deirl'torod'leas
`
`3W Mai'lrederylherra
`
`Stalillicd Andynis
`This study was not pourered. A large number of
`investigators participated in the trial to obtain a
`substantial body of evidence regarding the effec'
`tiveness and safety ofdoxvcycline 40 mg when used
`in normal dermatologic practice. As discontinu-
`ation rates in a large openJabeI trial were antici-
`pared to be relatively high compared with smaller
`controlled trials. the per-protocol (PP) population
`was selected a priori for all effectiveness analyses.
`The PP population consisted of all participants
`who completed the 12-week trial without major
`maximum]. Baseline 102‘ stores were compared
`protocol deviations. The safety population was
`with subsequent IGA scores using the Cochran-
`defined as all participants who received at least
`Mantel-l-laenszel (CMl-l) test. Similarly, baseline
`1 dose of the study drug. Discrete variables such as
`CEA scores were compared with subsequent CEA
`certain demographics, ABS. and categorical effec-
`tiveness were summarized by frequencies (number
`scores using the CMH test. The baseline dichoto-
`mized lGA scores were compared with subsequent
`and percentage). Continuous categorical effective-
`ness variables were summarized by mean, median,
`visits using the CMH test. Significance for all
`standard deviation. number. and range (minimum.
`hypotheses testing. except normal distribution, was
`W.UJTIS.OCM
`HUI-E 36. WP 2010 9
`wot-15min Nopl‘tdtiisnfloflimmqhem maammnmmmdum.
`
`Alsatian)
`
`Hawaiians
`
`
`
`

`

`Tables.
`
`PuticipantDemog'aphics
`Per-PlotooolPopulalim)
`
`
`Romy
`
`man-am
`
`Mean
`
`Ila-m
`Miwm
`
`503nm
`
`50.0
`
`mm 130.870
`
`Senna“
`
`Fannie
`
`We
`
`Mum
`
`591 (715
`
`2351285)
`
`I-Ispaicorlflho
`
`72m]
`
`Nell-Worm
`
`7541913;
`
`mum
`
`While
`
`763831)
`
`Mamm 610.?)
`
`Asian
`
`11:13
`
`WWW“ 15.1]
`
`Name Woe-er
`Panicm
`
`0310!
`
`WWW *1 (953
`
`I
`
`I
`
`I
`
`N
`
`V
`
`VI
`
`a (0.4)
`
`37 I45}
`
`a? an
`
`321 (sea
`
`275 (335)
`
`130 (15.7)
`
`30 5-6!
`
`3 [0-4)
`
`at «=95. For normal distribution testing, signifi-
`cance was III—‘1”.
`
`HEWLTS
`mm
`A total of 142.1 panicipanu from 271 investigation-l
`sites were mulled in the study with "97 partici-
`paminlhemorndaerapyarm.1hemnod1erapy
`Merv pawl-lion was composed of 1196 participants
`became a single enrollee withchew withoul receiving
`adaseofthemld'ydrug.0fd1e ll97ennoiled parv
`tieipanta. 826 (69.0%) completed the trial without a
`majorpmmeoldeviationandwereimhldedindlefi’
`analyse: {Table 3). The mean age of participant- in
`duispupdatinanOJ mmpanieipamwere
`women (71.5%). More than 90% afparticipam were
`whitearrdweremtainqaanicorlmjmedmic'
`iry. Mutparticipanuhad *in dutwasclauified as
`mnnalorcombimria'l type In thisgruip. the mean
`duration ddiaeme was 5.0 yearn.
`
`mmW
`Investigate»- Global ARM—Must PP partici-
`pants {74.6%} treated with mhrapy had clear
`(35.5%} or near clear (39.1%) [GA scores at week 12
`(Figure ILTI'Iere was asignificant difference between
`[he dint-Inner: of baseline ISA and week 12 [GA
`
`scores in the grown (P400011
`Clinicim Erythana AsusmmD—At week 12.
`74.5% (1‘ PP participant: fluted with modicum
`had CEA scores of none (17.7%) or mild (56.8%)
`(Fimre 2 I‘ There was a significant difference between
`the distriution afbaseline CEA and week 12 CEA
`
`more: in the group (P<.OOOI ).
`Pruponim of Tm! Responders—Winn sue-
`cela was defined as an [GA Ito": J clear, 35.5% of
`the momd'uetapy P? participants were mes-fill at
`week 12. When mee- was defined as an IGA more
`
`of clear or near clear. 74.6% of the PP pupuluinn
`was smfirl at week 12 (Figure 3).
`
`81mm
`Safety assessments were performed on “96 plaid-
`pantaurl‘nreeeivedat least I doledthe luxlydmg. In
`duemcmwtheupyufetypupalnticm.dnetewfletepom
`of 221 AB; in 143 participants (110%)an 4).
`TheAanu-e mainlylnildarlnoderateh'lsewrity.
`Of all AB in the monm‘l'herapy safety population,
`mpulkipannhad AB: hvalved withthegasunintes-
`tinal trad; afthae, 3.6% were maiden-d to be pos-
`sibly (n: 23), probably (n=10}, or definitely [11:10)
`mktedmdaemdydrugmereeruqumnafvul-
`vovaginal candidiasil {0.1%} and 1 report of oral
`candidial'a (01%}: 5 reporu acid as fungi infec'
`lion (andfin‘tl'fldauifiedasyean infectiona)(0.4%);
`W.Q.II'|SOCIJ
`
`100.1119.
`mmmiumumdmmmyummmmmagi-mamas: Hm.
`
`
`
`

`

`
`
`matmdmmmmmamwmmnmmm-
`mwmflvnnmmmmmmmmmmmm
`“mmmmmdm128Amasm'mmawmtpemn
`
`prmryfealmecfrouaeea,almwaamlulted intl'le
`
`and I report of a pl'notnlerm'tiviq reaction (0.1%)
`in dieufety population. Eighty participants (6.7%)
`diaemdnmdthenudyuutmembeunxdmfi
`finnhmhfilnwfiehlmtbnmbuhhm
`pinliminnfnrpulihle
`accident anewdraguuofhmcarceronmline
`
`noun: of the trul dam-natal: reduction of this
`disease midterm time; CEA semen of moderate
`mmmumhhaddeuenmdmmor
`mild in approximately 1'5““: of participanu by d'le end
`oldie study.
`lzarildr an the existing evi-
`trial
`The present
`dence of the efledivemu and safety all once-
`daily minim-tier: of dnxycycliue 10 mg in
`participants with men. The 40—01; once-daily
`TheORCAuiali-d‘clargmmuhlflcd
`formulation was approved laced on two 1M.
`madamltdemomtratudutdueflmgformulldon
`dduxchlhwewaaell'ectiveumomhenpyinpur—
`randomized. phase 3 clinical trials.“ Puticipuntr in
`both studies (14:53?” had moderate to severe
`ridpann with mild msevere rm. lnvertlwon
`meaeddieaeverityafdiieaaeinamrdntflu
`mllfl—Wmlummlfisz rindules)and
`were treated with either the surly dag (“=269)
`well in clinical practice by clarifying it by overall
`or placebo {IF—'26”. Cunpled with placebo, the
`neverilyateachviriLDmingtbecmal'dieuial,
`”Nations in both undies had tignificmt reduc—
`BAmimprovedmddmchmge-melhflully
`tinnl in mean lesion 0mm (P4901). The dillero
`and statistically significant (fl-(”WU By the end
`encelwetweenllleefl'lcacyolmldydngandplaeebo
`ol'thetrial. Wv7s%dwtidwflbhld
`anmnnlesiuummldheoheweduurlyu
`uchievcdelenturneatcleulGA mu.Etyd1ema.a
`WWWWTBIW
`WH.WMO 11
`Cami-tannin.mmdmmmhmmmmmuwmmdnm.
`
`
`
`

`

`
`
`MZWMMWWMMHMMMthmw-
`mmmeMmmmmwmmmmam
`“mammmmdmmmmnmmammpenmu.
`
`week 3andoontinuedtodivergeford1eremainderol
`themrdy. Tl'teoverallhenefilaoftrearmcntpeuhted
`throughweel: 20inperticipmmwhowereevalmted
`4 week: after treatment had been discontinued.“
`A I'm-tam of the 2 trielr demon-traced that
`the efficacy oidtuycycline 40 In; confers elinitally
`Iignificant anti-inflammatory ellitzacyr in meet"
`A rarflomined, double-blind, parallel-pulp, nul-
`ticenta'mrdyalrohasoonpared theemcacyand
`Iafety of once thily mhantilnicrohialddore doxy-
`eydine 40 ms “1:44) with eonverttiunal :10:er-
`eiiru: 100 mg (11:47) in participant: with moderate
`to severe tomcat.m Raul:- ol the trial deunnunted
`that the end-inflammatory client of treatment with
`ruhantirnicrohial-dme dmycycline in the 40ml; for-
`mulation produced eqtivalent decreanen in inflam-
`matory lesion counla and CEA scores. Fmthermore,
`penicilnnu treated with the unique formulxion
`lad a 540“ lower incidence of mime-tine]
`tnet Alia,“
`
`setting. Large-scale, randomized, controlled tri-
`alr have provided evidence to guide clinician: in
`thetrentmentofanrietyofdiwtdenofdte-kin
`andathctorgnneyuemazlmmetnhuehuhem
`a recent tecognitim thet mmmiwvbued clini-
`cian- Ihculd help guide and participate in clinical
`trials.” These studies mayr include large number!
`of patients seen and treated in continuity settings,
`enabling investigators to confirm the effectiveness
`of various interventions, answer questioru about uti-
`lization. end help identify uncommon a' new AF...
`ThemdtxoltheORCAtti-nlptovideaddifimal
`upper-t on the benefit: and ufety at this treatment
`that were first reported in the phase 3 trials.“ Poten-
`tial limitations of this trial include choice of the
`specific mrconu: meanlres and decision to nae the
`PP population for the primary analylea. Aim
`medthePPparticilnnuwouldexclulethem
`serioupeotoenlviolatiutthwulectetluthe
`primary outcome me dining delign ofthe study
`because larger number: of participant dropout:
`”allot protocol deviations were expected in this
`W.Qfl|fi.€(fl
`
`Key fcuutu ofthe elm-mt trill include the large
`uieeoftheuudypowlatiunanditeemmity-heed
`reams-
`mmmtnmmdfismmum med. Immahwmmafl Pt”.
`
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`Wmmmmxmfimmawmmmmum
`inmfl’cMWmMWMaflJMMwmmmbmmmm
`mummmmmrwmmmmmmzm.
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`qpcofuisl.0vanll,lhcmltsdfl1hhillnllc
`I MM mmfilmtinn to the evidence bale
`that his Incumhtcd than the candivmm and
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`mum
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`Themlud'lhismdyindicatcfiat lZwoch
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`for her upper: in the marina of flak article.
`Her wot-k wan fimdcd by Calcium- Labunuics.
`LRThnimaI-omldlikcmuhmldgelm
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