RU 486 in normal women
`Effects of the antiprogesterone
`
`in the midluteal
`phase
`administration
`I.Single-dose
`
`M.D., Pekka Lahteenmaki,
`M.D.,
`M.D., Daniel R. Mishell, Jr.,
`Donna Shoupe,
`M.D., and
`Hosam Madkour,
`M.D., Lars Birgerson, M.D.,
`Oskari Heikiobeimo,
`M. Spitz, M.D.
`Irving
`F_inland
`and Helsinki,
`Los Angeles, California, New York, New York, Up,psala, Sweden,
`
`phase in
`In the midlu!eal
`AU 486 was studied
`oral dose of the antiprogesterone
`to a single
`The response
`and 800 mg RU 486 on days 6 to 8 after the
`a dose between 50
`received
`women. Each subject
`26 normal
`group of
`Another
`48 hours.
`were taken over the following
`surge and blood samples
`hormone
`luteinizing
`for 14 days.
`was eXjended
`of 200 mg RU 486 and blood sampling
`oral dose
`a single
`received
`five patients
`patient
`Two distinct
`3 days after RU 486 administration.
`in all women but one within
`Menses were Induced
`In nine of the subjects
`emerged.
`populations
`and the treatment
`cycle
`episode
`bleeding
`. there W<!S a single
`bleeding
`a second
`In 16 of these 25 patients
`cycle.
`(p < 0.05) than the fo11ow!ng
`was significantly
`shorter
`treatment
`cycle was
`The total
`surge.
`occurred 19.0 :: 0.8 days after the luteinizing
`hormone
`episode
`In the group with a single
`cycle.
`(p < 0.05) when compared with the following
`prolonged
`significantly
`estradiol,
`in follicle-stimulating
`and
`hormone,
`there was a significant
`decline
`episode,
`bleeding
`in the group wilh
`in these values
`tiut there was no change
`period,
`sampling
`progesterone over
`the 48-hour
`serum
`on the basis of RU 486 dose or
`could no.t be separated
`These two groups
`epis!)des.
`two bleeding
`There were no
`rise in serum prolaciln.
`there was a dose-dependent
`doses,
`the four higher
`After
`levels.
`Increase
`with the three lower d�s. but there ...;as a significant
`at 24
`values
`in mean cortisol
`alterations
`1 and 4 hours and
`between
`of AU 486 were maximal
`Serum levels
`doses.
`and 48 hours after the higher
`(AM J 08STET.GYN�C<?L 1987;157:1415·20.)
`to be 24 hours.
`of serum AU 486 was detennined
`the half-life
`
`gonadotropins, steroids
`Key words: RU 486; contraception,
`
`of RU 486, a 19-
`and development
`The synthesis
`oral dose of RU 486,
`After a single
`activity.
`ticoid
`in adrenocorticotropic
`increase
`ihere is a transient
`a major breall.­
`is considered
`derivative,
`norprogestin
`and has opened a
`endocrinology'
`in steroid
`through
`hormone.'·'
`Beyond its potential
`use in
`control.
`new era in fertility
`the effect
`of
`The aim of this study was to investigate
`the antiprogestational'
`and
`technology,
`contraceptive
`gonadotropin,
`oral dose of RU 486 on bleeding,
`a single
`... activities
`antiglucocorticoid
`of RU 486 serve
`as a
`women in the
`given to healthy
`patterns
`and steroid
`the pharmacodynamics
`phase. In addition,
`midluteal
`of hormone action.
`unique tool for investigation
`devel­
`with a recently
`were studied
`of this compound
`RU 486 has been noted to interrupt
`Ip early repons,
`oped radioimmunoassay.
`and to
`and in monkeys•
`phase in women'-6
`the luteal
`RU 486 has also been
`early pregnancy.'·•
`terminate
`for the glucocorticoid
`recep:
`shown to have an affinity
`and methods
`Mat.erlal
`whose ages ranged from
`healthy women,
`Thirty-one
`than that of dexa­
`tor that is about four times higher
`for participation
`in this
`were selected
`22 to 35 years,
`and has been shown to have antiglucocor-
`methasone
`(28 ± 3 days)
`cycles
`menstrual
`They had regular
`study.
`They
`15% of their ideal body weight.
`and were within
`Endocrinology, Department
`of
`of Rtfrroductiw
`from Ult Seclion
`or had used a bar­
`sterilized
`had been surgically
`�ithe�
`of StnJ.lllem California,
`University
`and Gynecology,
`Obstetrics
`The volunteers
`had not
`rier method for contraception.
`Popu/JJJion Coun­
`Research,
`Ult Cmter for 8iomtdual
`los Angtks,
`a11d GynecologJ , Uni­
`of Obstetrics
`cil, Nnu York, Im Dtportmenl
`medication within the
`last 6 months.
`taken any steroid
`Laboratory,
`Rest(J.rch
`and Ult Steroid
`Uppsola,
`vmity Hospital,
`cyde, each patient
`On the tenth day of the menstrual
`of 1-ltlsinlu..
`University
`of Media,/ Chnnistry,
`Dtportm,mt
`for determi­
`began to undergo daily blood sampling
`Foundations.
`in part by grants from Im Ford and Mt/Ion
`Supporud
`by lht CLINFO projed
`was provided
`assi<lanu
`Ctnnpulationai
`hormone (LH)
`nation of the day of the luteinizing
`Resourus of the Nationol
`fo.
`funded by the Division of Research
`the vol­
`th<: LH surge,
`Six to eight days after
`s�rge.
`Grimt No. RR-0004].
`of lltalJh,
`stitultJ
`at 7:30 AM, after an over­
`were asked to report
`unteers
`of the Society for
`Annual Mttting
`al Ult Thiri,-second
`Presenled
`Morch 20-2J,
`1985.
`lnV<lligaJion, Phomix, Arizona,
`Gyneoologie
`after midnight
`from smoking
`and to refrain
`night fast,
`Hospilal Room
`M.D., Women's
`Rl!/Jrinl requests: Donna Shoupe,
`medication.
`for administr.ition of
`CA 900JJ.
`Missum Road, los Angtks,
`IA46, 1240 Norll1
`
`1415
`
`T. Alfaro
`Corcept Therapeutics, Inc.
`Exhibit 2013
`Neptune Generics, LLC v. Corcept Therapeutics, Inc.
`Case IPR2018-01494
`Ex. 2013-0001
`
`

`

`1416 Shoupe et ai.
`
`December 193?
`Am] Obstet Gynecol
`
` ll.0|’g1
`
`9.0
`
`0 Ln,
`
`L”
`qu/ml
`
`7.0 l
`
`5.0
`
`30
`
`l
`
`O
`
`l
`
`2
`
`6
`4
`HOURS
`
`s_|_fl_l__.l
`to
`24
`45
`
`FSH
`mlu/rnl
`
`6.0 .l‘
`4.0 Klee-JR;
`2.0
`
`0 FSH.
`
`v ts",
`
`.
`
`l‘
`
`0
`
`l
`
`2
`
`6
`4
`HOURS
`
`IO
`
`24
`
`43
`
`Fig. 1. LH (upper panel) and FSH (tottrer panel) values after a
`single oral dose of RU 486 ranging from 50 to 800 mg. LH,
`and FSH; refer to the patients with one bleeding episode after
`RU 436 administration and ”hand Ft'ilil'z refer to patients
`having two bleeding episodes. No significant changes in LH
`were noted in either group. Analysis of variance detected a
`significant decrease in FSH, (p < 0.001} overthe 43-hoursam-
`pling period.
`
`Subjects received either 50, 100. 200, 400, 600. or
`800 mg of RU 486 (50 mg tablets supplied by Roussel-
`Uclaf. Romainville, France) at 8:00 AM. All groups com-
`prised four subjects except for the two highest-dose
`schedules where five subjects were studied in each
`group. No smoking or food was permitted for 4 hours
`after ingestion of the medication and vital signs were
`recorded every 30 minutes for 6 hours. Blood samples
`were obtained through an indwelling catheter at — V2,
`0 + V2. 1. 2. 4. 6, [0. 24, and 48 hours. A further group
`of five subjects received 200 mg as a single oral dose
`and blood sampling was continued daily for I week and
`then was performed at 10 and 14 days (extended sam-
`pling group}.
`These blood samples were assayed for pmlactin, es-
`tradiol, progesterone, cortisol, LH, follicle—stimulating
`hormone (FSH), and RU 486 by previously described
`radioirnrnunoassay methods?” Normal serum AM cor-
`tisol values are 10 to 3D ugldl. Two different radio-
`immunoassays were used to measure RU 486. The first
`was the method of Salmon and Mouren." The second
`utilizes chromosorb column chromatography.12 This
`latter, more specific assay was used only to measure
`RU 436 levels in the samples from the extended sam-
`
`
`
`MD
`
`"3.0
`
`6.0
`
`I 5‘1
`0 Pl
`
`0
`
`l
`
`2
`
`6
`4
`HOURS
`
`lo
`
`24
`
`45
`
`Fig. 2. Upprrpanal: Estradiol (5,} values after a single oral dosn
`of RU 485 ranging from 50 to 800 mg. it}! refers to patient
`with one bleeding episode after RU 486 administration ant
`£32 refers to those with two bleeding episodes. Analysis 0
`variance detected a significant decrease in £2! (p < 0.05] ove
`the 48-hour sampling period. Lower panel: Progesterone (P;
`values after a single oral dose of RU 486 ranging from 50 to
`300 mg. Pi refers to patients with one bleeding episode after
`RU 486 administration and P, refers to those with two bleed—
`ing episodes. Analysis of variance detected a significant de-
`crease in P, {p 4' 0.005) over the 48—hour sampling period.
`
`pling group. The antiserum against RU 486 used in
`both assays was donated by Roussel-Uciaf. In addition.
`SMA- is and complete blood caunt were performed at
`0. 4. 10. 24. and 43 hours.
`'
`Results were analyzed by analysis of variance with the
`use of'BMDP Statistical Software." One- and two-way
`analysis of variance and Student's t test were used to
`determine statistical differences between groups.
`
`Results
`
`Clinical features. Menses commenced in all patients
`but one within 1 to 3 days after RU 485 administration
`(Table I}. in nine of these 25 subjects (two who received
`50 mg. two who received 100 mg, one who received
`200 mg. one who received 400 mg, and three in the
`800 mg group), this represented the only bleeding cp-
`isode. The mean length of the treatment cycle in these
`nine subjects was significantly less (p < 0.05) than that
`of the following cycle (Table 1).
`
`Ex. 2013-0002
`
`Ex. 2013-0002
`
`

`

`Volume 15'?
`Number 6
`
`Effects of RU 486 in normal women. |
`
`141?
`
`In the remaining 16 subjects. a second bleeding ep-
`isode was reported. In these subjects the initial bleeding
`episode occurred at a similar time after the LH surge
`as in the previous group. but the duration of bleeding
`was significantly shorter (p < 0.05). The full duration
`of the treatment cycle in those subjects who had two
`bleeding episodes (with the onset of the second bleed—
`ing episode used as a reference) was 32.9 x 1.} days.
`This was longer (p < 0.05) than the following cycle (Ta-
`ble 1).
`In none of these subjects were any adverse effects
`encountered. Furthermore, electrolytes, hepatic func-
`tion, and blood count did not change in any subject.
`In one subject who received the 600 mg dase, bleeding
`did not occur until 56 days after treatment.
`Hormonal parameters. The hormonal profiles of
`four patients (two from each group} were excluded
`from analysis because of incomplete data. In those 14
`subjects who had two bleeding episodes. there was no
`change in serum LH. FSH. estradiol. or progesterone
`over the 48—hour sampling period. However. in those
`seven subjects who had a single bleeding episode, anal-
`ysis of variance showed a significant decline in estra-
`diol (p c 0.05), FSH [p < 0.001). and progesterone
`{p < 0.005} (Figs.
`1 and 2).
`I
`There were no significant changes in LH, FSH. es-
`tradiol, or progesterone when hormonal results were
`expressed according to the dosage schedule of RU 486
`and independent of the bleeding pattern. Analysis of
`variance showed that there was a significant increase in
`prolactin (p < 0.05) with the 50, 200, 400, and 800 mg
`dosages. When compared with the pretreatment levels,
`the peak values were greatest between 4 and 6 hours
`{p <: 0.05). Values returned to normal by 24 hours
`(Fig. 3).
`Analysis of variance showed a significant increase
`(p < 0.05) in mean cortisol values after the 100. 400,
`600. and 300 mg doses. When compared with baseline
`values, the cortisol level rose significantly (p < 0.05) at
`24 hoursafter the 600. and 800 mg doses and at 48
`. hours with all three higher doses (Fig. 4).
`RU 486 levels. When measured directly after di-
`ethylether extraction,
`the serum levels of RU 486
`reached a maximum between I and 4 hours after inges-
`tion of all doses (Fig. 5). All RU 486 levels were sig-
`nificantly lower with the 50 mg dose than with the five
`higher-dose regimens (p < 0.05). The RU 486 levels at
`6. 24, and 48 hours were also significantly lower after
`the 100 mg dose than with the four higher doses
`(p < 0.05). RU 486 levels were Lhe same with doses of
`200 to 800 mg. With doses of 3200 mg, mean serum
`RU 486 levels fell minimally. and even after 48 hours
`values were still above 1.4 ugfml. On the other hand,
`after the 50 and 100 mg doses. RU 436 values did
`decrease and were under 0.4 uglml at 48 hours. There
`
`PR1.
`rig/ml
`
`l 800 mg
`
`
`
`HOURS
`
`Fig. 3. Prolactin (PRL) levels after a single oral dose of
`RU 486 ranging from 50 to 300 mg. Analysis of variance
`detected a significant increase in PR1. after the 50, 200. 400.
`and 800 mg doses. at p C 0.05 increase over baseline values as
`determined by the paired t test.
`
`were no differences in the RU 486 levels between the
`
`groups with one or two bleeding episodes.
`The serum levels of RU 486 in the extended samp-
`ling group are shown in Figs. 5 to 6. Chromosorb col—
`umn chromatography was used in these samples and
`the values were lower than those with corresponding
`200 mg dosage schedule. Nevertheless, after 4 hours
`the disappearance curves with both assays were par-
`allel. Presumably.
`the values after chromatography
`represent true RU 485 concentrations. The half—
`disappearance time was 24- hours (Fig. 6).
`
`Comment
`
`. Administration of RU 486 as a single oral dose from
`50 to 800 mg in the early Iuteal phase was well tolerated.
`The induction of menses within 3 days is in accordance
`with results of previous studiesfiet ‘5 This vaginal bleed-
`ing. which occurred despite high levels ofestracliol and
`progesterone. implies that RU 486 acts directly on the
`endometrium to produce shedding regardless of any
`effect it may have on hormonal levels. A similar bleed-
`ing pattern has also been documented in nonpregnant
`women during concomitant treatment with RU 486 and
`human chorionic gonadotropin in the luteal phase?"
`A total of 33% of our subjects displayed only a single
`
`Ex. 2013-0003
`
`Ex. 2013-0003
`
`

`

`1415 Shoupe at at.
`
`December 198?
`Arr: ] Obstet Gynecol
`
`AM.
`CORTISOL
`149/ 6'
`
`30
`
`20
`
`10
`
`30
`
`20
`
`10
`
`
`
`lamina
`Booting
`“looting
`
`azaflmg
`OlDOmg
`ISOmg
`
`00124
`
`6
`HOURS
`
`102448
`
`Fig. 4. Cortisol values after a single dose of RU 436 ranging from 50 to 800 mg. Analysis of variance
`detected a significant increase in cortisol {p c 0.05) after the 100. 4-00. 600. and 800 mg dose.
`- p < 0.05 increase over baseline values as determined by the paired t test.
`
`RU 486
`its/ml
`
`I 50mg
`
`I200“
`v 200M EflTEND
`3100119
`
`HOURS
`
`Fig. 5. RU 486 levels aftera single oral dose of RU 486 ranging
`from 50 to 800 mg. Analysis ofvariance detected that all points
`after 50 mg dose and at 6. 24, and 48 hours after the 100 mg
`dose were significantly lower (p < 0.05) than values after the
`higher doses. The 200 mg extend refers to the extended sam—
`pling group that is also depicted in Fig. 5.
`
`bleeding episode, whereas in the remaining subjects a
`second bleeding episode occurred. This phenomenon
`appeared to be independent of the dose or serum con-
`centration of RU 486. The hormonal profile in these
`two groups was distinctly differenL In those subjects
`
`with two bleeding episodes there were no changes in
`LH. estradiol. or progesterone levels. In addition. if the
`commencement of the second bleeding episode is re-
`garded as the termination of the cycle, the luteal phase
`appeared to be prolonged by RU 486. In contrast, in
`those subjects who had a single bleeding episode there
`was a progressive significant decline in serum FSH.
`estradiol. and progesterone levels over 48 hours ofsam-
`pling time with a concomitant shortening of the luteal
`phase and cycle length. This suggests that under certain
`circumstances RU 486 can be luteolytic. Similar obser-
`vatiOns have been made by other workers.“ 1‘ Although
`it is possible that the decline in steroid levels may rep-
`resent the fall seen in the latter part of the normal
`menstrual cycle, this is unlikely since no corresponding
`fall occurred in the group with two bleeding episodes.
`The decrease in the serum progesterone level could
`be related to a direct action of RU 486 on ovarian
`steroidogenesis.” However, it could also represent an
`effect on the hypothalamic-pituitary axis. We did ob—
`serve a decrease in FSH in one group of patients but
`were unable to detect a decrease in LH secretion. Re-
`cently, with more frequent sampling we also observed
`a reduction in amplitude and frequency of LH pulses
`during RU 486 administration in the luteal phase."
`Other workers have also described a reduction in LH
`
`pulse amplitude consequent to RU 486."
`Nienian ct al.‘ observed menstrual bleeding in nor—
`mal women within 72 hours of a single oral dose of
`RU 486 (10 nigi'kg body weight) given in the midluteal
`phase. In the patients treated with RU 436 on luteal
`day 7. they report adecrease in the serum progesterone
`level by luteal phase day 10 and the onset of vaginal
`
`EX. 2013-0004
`
`Ex. 2013-0004
`
`

`

`Volume 15?
`Number 6
`
`Effects of Flu 486 In normal women. I
`
`1419
`
`RU486 pgfml
`
`3.0
`2.0
`
`1.0
`
`0.5
`
`0.2
`
`0.1
`
`0.05
`
`0.02
`
`0.01
`
`0.005
`
`0.002
`
`0.001
`
`6
`
`8
`
`10
`
`12
`
`14
`
`DAYS
`
`Fig. 6. RU 436 levels in the extended sampling group after a single oral dose of 200 mg RU 486.
`The half-life of RU 486 is 24 hours.
`
`Table I.» Effects of RC 486 administration
`
`Porttreatment 01d:
`Treatment cycle
`Days of
`Onset
`Bleeding
`length (days)
`Length (days)
`binding
`(day: after LH surge)
`N
`episodss
`34.0 :- 2.I
`25.2 i 1.4*
`3.4 1 0.3
`9.8 1 0.5
`9
`1
`26.0 1 1.7
`32.9 1 LI
`6.0 I 0.3?
`9.6 i 0.5
`16
`2
`
`19.0 1 0.8 4.2 3 0.3
`Values are mean 1 SD.
`
`‘9 < 0.05 when compared with positreatrnent cycle length.
`7p c. 0.05 when compared with group with one bleeding episode.
`
`bleeding within 72 hours of treatment in all patients.
`They also described two patient groups as regards to
`the onset of menses, which may correlate with our two
`patient groups.
`Circulating RU 486 levels measured by immunoassay
`showed that this synthetic steroid was absorbed rapidly.
`Doses of 50 and 100 mg gave lower blood levels than
`higher doses. However, no clear dose response was ev-
`ident since 200 to 800 mg RU 486 gave similar blood
`levels. The immunoassay used to determine these cir-
`culating levels is nonspecific and measures metabolites,
`including the monodemethylated and didemethylated
`compounds as well as Lhe alcoholic derivative.’ '- " These
`metabolites seem to have a smaller biologic activity.'9
`For this reason we developed a more specific radio—
`immunoassay using preliminary chromosorb chroma—
`tography. With this modification, values were lower but
`gave a parallel disappearance curve. Values of RU 485
`meaSure-d by immunoassay after chromosorb chro-
`
`matography give values similar to those determined by
`high-presm re liquid chromatography." The half-life of
`RU 486 was 24 hours. The long half-disappearance of
`RU 486 suggests that there is binding to plasma pro-
`teins. Recent studies have shown that RU 486 binds to
`
`an u.-globulin."
`The late rise in cortisol, noted at 24 and 48 hours
`after ingestion of the 400, 600. and 800 mg doses, sug-
`gests the presence of a mild degree of antiglucocorti-
`coid activity with these doses. Nevertheless. mean val-
`ues remained within the normal range. The late in-
`crease seen after 24 and 48 hours, without an}r change
`during the initial 10 daytime hours after ingestion of
`the drug, would be consistent Iwith the work of Gaillard
`et al.,°-‘ who demonstrated that the antiglucocorticoid
`activity is seen only during the early morning hours
`when adrenocorticotmpic harmone secretion is high.
`Rakoff and Yen" reported a transient
`increase
`in prolactin in estrogen-primed women receiving in-
`
`Ex. 2013-0005
`
`Ex. 2013-0005
`
`

`

`1420 Shoupe at al.
`
`December 1967
`Am ] Obstet Gynecol
`
`tramuscular progesterone after oophorectomy. This
`would imply a positive effect of progesterone on pro-
`lactin secretion. which is in contrast to the transient
`increase in proiactin we noted after treatment with an
`antiprogesterone. Healy et al.“ described a decrease in
`prolactin after treatment with RU 486 in monkeys {10
`mgfkgl.“ However. these were castrated moo keys who
`had steroid replacement via estradiol and progesterone
`capsules. which produce basal hyperprolactinemia.
`Within 1 hour after parenteral RU 486 administra-
`tion. these elevated prolactin levels were decreased.
`Thus the effect of RU 436 on prolacu'n secretion varies
`and may depend on the mode of its administration.
`the dose. the species, and the prevailing steroid con-
`centrations.
`
`The reason why two subgroups emerged in this study
`is not evident. They could be differentiated by both
`bleeding patterns and hormonal levels. Both groups
`received RU 486 on days 6 to B after the LH surge and
`there were no differences in RU 486 serum levels be-
`tween the two groups. Thus these two patterns of re-
`sponse could not be differentiated on the basis of time
`of treatment. dosage of RU 486, or circulating RU 486
`levels.
`_
`RU 486 has been proposed as a cocoa-month pill.6
`Our data would support the value of RU 486 for this
`use. However. the emergence of two patient groups
`suggests that further characterization of these distinc-
`tive patterns is necessary.
`
`REFERENCES
`
`l. Teutsch G. Analogues of RU 436 for the mapping of the
`progmtin receptor: synthetic and structural aspects. In:
`Baulieu EE, Sega] S]. eds. The antiprogesterooe steroid
`RU 436 and human fertility control. New York: Plenum
`Press, 1985:2747.
`2. Healy DI... Chrousos G. Schulte HM. Gold PW. Hodgen
`GD. Increased adrcoocorticotropin. cortisol. and arginine
`vasopressin secretion in primates after the antiglucocor-
`ticoid steroid RU 486: dose response relationshipj Clio
`Endocrinol Metab 1985 :66: l.
`3. Gaillard RC, Riondel A. Muller AF, Herrmarm W. Baulieu
`EE. RU 436: a steroid with antiglucocorticoid activity that
`only disinhibits the human pituitary-adrenal system at a
`specific titoe of day. Proc Natl Acad Sci USA 1934;
`SI :3379.
`4. Hermann W. Wyss R. Riondcl A. et al. The effects of an
`antiprogesterone steroid on women: interruption of the
`menstrual cycle and of early pregnancy. 3 R Acad Sci
`[III] 1982;294:933.
`5. Shoupe D. Mishell DR, Lacarra M. Gutierrez 1-2, Lahtoen—
`malti P. Spitz L Endocrinologic effects of the antiproges-
`terone RU 486 in the luteal phase of normal women. In:
`Baulieu EE. Segal SJ. eds. The antiprogesterone steroid
`
`RU 486 and human fertility control. New York: Plenum
`Press. 1965:285-93.
`Niemao LK. Che-ate TM. Chrousos GP. et al. The pro—
`gesterone antagonist RU 486: a potential new contracep-
`tive agent. N Engl] Med 198?:316:187.
`Haspels AA. Interruption of early pregnancy by an an-
`tiprogestational compound. RU 436. Eur] Obstet Gynecol
`Reprod Biol 1985;20:169.
`Mishell DR. Shoupe D. Brenner PF, HOrenstein j, La-
`carra M. Spitz 1M. Termination of early gestation with
`the anti-progesterone. RU 486. Contraception 1987;
`35:307.
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`
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`
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