EX2240
`Eli Lilly & Co. v. Teva Pharms. Int'l GMBH
`IPR2018-01712
`
`1
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`

`

`7c
`
`CEPHALALGIA 15 (1995)
`
`3. Substances which can cause an attack of min
`graine or an attack of other vascular headaches do so
`by stimulating one or more steps in the NO—CGMP
`pathway or by exerting effects which are agonistic
`to those of one or more steps in this pathway.
`Although there are data to suggest these hypothe—
`ses they cannot be regarded as proven. But
`the
`hypotheses are readily testable. There follows argu—
`ments in support of each of the three parts of our
`overall hypothesis.
`
`Support for the first part of the hypothesis
`Histamine and glyceryl trinitrate (GTN) reliably and
`dose dependently produce headache in normal vol—
`unteers and migraine sufferers
`(15—17)
`(Fig.
`I).
`Glyceryl trinitrate itself has no known action in the
`human body but acts via liberation of NO and is
`thus regarded as an NO donor (18—21). The drug is
`suited for
`experimental
`studies of NO—induced
`headache because it
`is well
`tolerated and diffuses
`freely across membranes owing to its lipid solubility.
`Thus it delivers NO to vascular tissues including
`those protected by the blood brain barrier. Histamine
`also appears to induce headache via NO. In human
`cerebral blood vessels it stimulates an endothelial I-IT
`receptor which probably activates nitric oxide syn—
`thase (NOS), the enzyme which catalyzes formation
`of NO from L—arginine (2.2, 23). Histamine thus
`stimulates
`the
`endogenous
`formation
`of NO,
`
`Day 1
`
`H‘w
`
`2.5
`
`2.0
`
`.4 U1
`
`‘0
`
`0.5
`
`0
`
`
`
`Headachescore
`
`|_L_l
`I_.L_1
`I._I_l
`;L_i
`|._J_J
`O
`20 0
`20 O
`20 0
`20 0
`20 Minutes
`Placebo
`uglkg/min
`
`1.0
`
`2.0
`
`0.25
`
`0.5
`
`Fig. I. Mean headache scores (0—10 scale) during and after four
`doses of intravenous glycery] trinitrate in normal headache~free
`subjects on day I of two separate study days. Glyceryl trinitrate
`was infused for 10 min, and during this period a rapid increase
`in headache was observed. This was followed by a 10-min
`wash-out period, which resulted in a rapid decrease in headache.
`There was a relatively low day-to-day variation and a ceiling
`effect at approximately 0.5 ug/kg/min. Reproduced with per-
`mission. from Ref. 16.
`
`NO in migraine
`
`95
`
`whereas GTN delivers NO directly. Most studies
`supporting a role for NO in migraine pathophysiol—
`ogy have used CTN (24—29). The following direct
`studies in humans support
`the concept
`that GTN
`induces headache by liberating NO:
`
`I. CTN—induced headache in normal subjects is
`short-lived and therefore is unlikely to be caused by
`other of its metabolites which have a longer half—life
`(16).
`2.. Isosorbide mononitrate has a long half-life and
`is not metabolized to S-nitrosothiols (30). It causes a
`long-lasting headache and long—lasting arterial dilata—
`tion in a dose—dependent fashion (17).
`3.--N—Acetylcysteine, which
`augments GTN
`effects in the heart by increasing the formation of
`NO or by enhancing the effect of NO itself, also
`augments the headache response to GTN and pro—
`longs arterial dilatation of the superficial
`temporal
`artery but not of the radial arteries (25).
`
`It thus seems likely that GTN induces headache via
`liberation of NO in non-migraineurs, but how rele~
`vant is this for migraine? It has been proposed that
`only subjects with a
`family history of migraine
`develop migraine—like CTN—induced headache (24),
`although this response is not an all or nothing
`phenomenon (16, 17, 2.9). The headache induced in
`non-migraineurs varies from absence in some indi-
`viduals to mild or moderate intensity. Headache
`rapidly diminishes after GTN infusion stops and
`disappears after 10—20 min. The response is dose-
`dependent up to 0.5 ug/kg/min, after which a ceiling
`effect
`is observed so that higher doses do not
`increase headache intensity (16). In non—migraineurs
`the headache has some of the features of a migraine
`attack but differs by being milder and without nau—
`sea, photophobia and phonophobia (17). In migraine
`sufferers the response is different. In a recent study
`(29) comparing 17 headacheefree controls
`to 17
`migraine sufferers, the latter group developed a sig-
`nificantly stronger headache with more migraine fea-
`tures than controls (Fig. 2.). The differences became
`more apparent at the end of the infusion. Thus, none
`of
`the
`control
`subjects
`developed
`significant
`headache
`after
`the
`initial headache had gone,
`whereas the migraine sufferers either had no relief of
`headache or had an initial
`relief
`followed by a
`Subsequent worsening. Within 24 h after infusion 11
`migraine
`sufferers
`developed
`typical migraine
`whereas no control subjects developed headache.
`Fourteen of the migraine sufferers, but no control
`subjects,
`took sumatriptan for
`the post—infusion
`headache.
`In this
`study details of post—infusion
`headache and accompanying symptoms were not
`recorded.
`In
`another
`study, hourly prospective
`recordings were made of headache characteristics and
`accompanying symptoms during 12h after intra—
`
`l l l
`
`2
`
`

`

`
`___..—-—
`
`
`96
`
`I Olesen et a1.
`
`5
`
`A
`
`Eg
`
`3
`
`In
`II!J:u
`s 2
`3
`I
`
`I
`
`0
`
`
`
`—4—— Migraine
`—+— Tension — type
`
`--*-- Control
`
`
`
`—+
`
`4+
`
`"what" .
`
`60
`
`80
`
`
`5
`—
`'1:-*-*-*
`*_*.*.*
`*
`_
`"*'
`ED
`1.0
`Minutes
`120
`0.015
`0.03
`0.25
`0.5
`Post
`Fig. 2. Mean headache intensity over time during four doses of
`glyceryl
`trinitrate (CTN)
`in migraine patients,
`tension—type
`headache sufferers and healthy subjects. Headache increased
`significantly above baseline after 35 min in all
`three groups.
`During doses above 0,015 ug/kg/min migraine patients experi—
`enced significantly more headache than controls (p < 0.05). In
`migraine patients the headache remained increased during the
`study period, whereas headache 60 min after the end of CTN
`infusion in both controls and tension-type headache patients
`was no different from baseline (p < 0.001 Kruskal Wallis, multi—
`ple range test p < 0.05). Reproduced with permission, from Ref.
`29.
`
`venous infusion of GTN 0.5 ug/kg/min or placebo
`for 20 min (27) (Fig. 3). The study was performed in
`10 sufferers of migraine without aura using a double—
`blind placebo controlled cross-over design. Eight
`patients developed headache during the CTN infu—
`sion but only one satisfied the migraine criteria
`during infusion. Eight patients developed a regular
`migraine attack fulfilling ll-IS criteria after GTN,
`however. Headache peaked at a mean of 5.5 h after
`
`
`
`Headachescore
`
`Nitroglycerin 0.5 ug x kg‘1 x min
`
`—'i
`
`
`
`Fig. 3, Comparison of the mean headache scores (0—10 scale) in
`response to glyceryl
`trinitrate (0.5 ug/kg/min for 20 min)
`in
`migraineurs (circles) and non-migraineurs (squares), Data from
`Refs 27 and 29. Figure reproduced from Olesen et al. TIPS
`19947151149253 with permission. 0 Nitroglycerin-induced
`headache in migraine sufferers and I normal subjects.
`
`CEPHALALGIA 15 (1995)
`
`pl
`
`the infusion (Table 1). The induced migraine attacks
`resembled the typical migraine attacks of the pa—
`tients. Of 5 patients who habitually suffered unilat«
`eral migraine, all developed unilateral attacks after
`GTN and of 3 patients who normally suffered bilat—
`eral migraine attacks all developed bilateral attacks
`after CTN. The accompanying symptoms experi—
`enced after GTN were also similar to usual accompa-
`nying symptoms. Only one placebo—treated patient
`developed a migraine attack.
`Where and how does NO act to cause an immedi—
`ate vascular headache as well as a subsequent mi—
`graine attack? Cerebral arteries, despite their blood—
`brain barrier, may be influenced by circulating vaso—
`active substances such as CGRP, 5HT, histamine for
`which there are endothelial receptors (31). Glyceryl
`trinitrate dilated cerebral arteries via release of CGRP
`(32)
`in one experimental study, other studies of
`animal and human material both in vitro and in vivo
`do not support this (33, 34). Because GTN degranu—
`lates mast cells and basophils (35), it might release
`histamine around dural blood vessels, where mast
`cells are abundant, but not around cerebral blood
`vessels, where they are scarce (36). Thus, GTN
`might
`induce headache by liberation of histamine.
`However, pretreatment of patients with the hiss
`tamine l-l, blocker mepyramine, which prevents his—
`tamine—induced headache (15), failed to prevent or
`even reduce CTN—induced headache (26). Nitric 0x-
`ide from GTN is therefore likely to exert its effect
`directly on cranial blood vessels or perivascular
`nerves or both.
`The type of cranial blood vessels
`involved is
`important. Since no changes occur in cerebral blood
`flow during attacks of migraine without aura,
`the
`arterioles which control flow seem to be unaffected
`(for a review see 37). In contrast, large intracranial
`arteries are dilated during attacks of migraine with
`and without aura (I, 3). Glyceryl trinitrate induces
`arterial dilatation demonstrated in intracranial arteries
`by transcranial Doppler and SPECT (38, 39) and in
`extracranial arteries by high frequency ultrasound
`determination of the superficial temporal artery di-
`ameter (17). Glyceryl
`trinitrate—induced arterial
`di—
`latation as well
`as headache is augmented by
`N—acetylcysteine pretreatment
`(25). Finally, middle
`cerebral artery dilatation induced by GTN was sig—
`nificantly greater in migraine sufferers than in normal
`subjects (28). Thus we believe the intracranial cere-
`bral arteries are the likely site of action of GTN to
`induce headache.
`When Ekbom gave 1 mg of nitroglycerin sublin—
`gually to 28 cluster headache patients during a
`cluster period, all patients developed a typical cluster
`headache attack with a latency of 30—50 min after
`administration (40). Subsequently, others have con-
`firmed the provocation of typical cluster headache
`attacks by nitroglycerin (41, 42). Histamine, proba—
`
`
`
`3
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`

`

`'6
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`T's—sme‘—e~——¢Hat
`
`ra-"re
`
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`
`CEPHALALGiA 15 (1995)
`
`NO in migraine
`
`97
`
`Table I. Clinical characteristics of: (a) Spontaneous migraine attacks, (b) headache during CTN infusion (20 min), and (c) peak
`headache post-CTN infusion.
`
`Subject
`
`Time
`
`Headache
`
`localization/intensity/quality
`Aggravated
`
`Accompanying sympt
`vomit/nausea/photo/phono
`(% of usual attacks)
`
`Migraine
`
`I a
`[3
`c
`2 a
`13
`c
`3 a
`b
`c
`4 a
`b
`c
`
`5 a
`b
`c
`6 a
`b
`c
`
`7 a
`in
`c
`
`8 a
`b
`c
`
`9 a
`b
`c
`10 a
`b
`c
`
`3
`
`3
`
`10
`
`3
`
`8
`
`6
`
`8
`
`5
`
`7
`
`right/severe/throb
`right/7/throb
`right/IO/throb
`right or left/severe/throb
`3ilat/3/throb
`.eft/S/throb
`right or left/severe/pres
`no headache
`.eft/9/pres
`bilat/severe/throb
`ailat/B/pres
`Jilat/ 1/throb
`
`bilat/severe/throb
`bilat/Z/throb
`Dilat/ 8/throb
`.eft/severe/throb
`eft/S/prob
`-eft/3/pres
`
`
`
`bilat/severe/throb
`bilat/Z/pres
`bilat/E/pres
`
`bilat/moclerate/throb
`bilat/I/throb
`no headache
`
`left or bilat/moderate/throb
`right/3/throb
`right/é/throb
`bilat/moderate/throb
`no headache
`bilat/slthrob
`
`yes
`
`yes
`no
`
`yes
`yes
`
`yes
`yes "
`
`no
`
`yes
`
`yes
`yes
`
`yes
`
`yes
`
`yes
`
`yes
`
`yes
`
`yes
`yes
`
`yes
`
`5 O%/ 100%/ 100%/ 100%
`no/yes/yes/no
`no/yes/yes/yes
`I%/20%/100%/100%
`no/no/no/no
`no/yes/yes/yes
`100%l100%/0%/0%
`
`no/yes/yes/yes
`100%/ 100%] 100%/100%
`no/no/no/no
`no/no/no/no
`
`O%/100%/100%/100%
`no/no/no/no
`no/yes/yes/yes
`100%l100%/100%/100%
`no/no/yes/no
`no/no/yes/yes
`
`o%/100%/100%/100%
`no/no/no/no
`no/yes/no/no
`
`0%/ 100%/100%/100%
`no/no/no/yes
`
`O%/O%/100%/100%
`no/no/yes/no
`no/yes/yes/no
`50%l100%/100%/100%
`
`no/yes/yes/yes
`
`yes
`yes
`yes
`yes
`no
`yes
`yes
`
`yes
`yes
`no
`no
`
`yes
`no
`yes
`yes
`no
`yes
`
`yes
`no
`yes
`
`yes
`no
`
`yes
`no
`yes
`yes
`
`yes
`
`GTN = nitroglycerin. Bilat = bilateral. Throb = throbbing. Pres = Pressing. Photo = photophobia. Phono = phonophobia.
`migr = fulfilling the [HS criteria for migraine without aura. Aggravated = headache aggravation by physical activity. Time = time
`to post-infusion peak in hours. From ref 27, with permission.
`
`bly via induction of cerebrovascular endogenous
`nitric oxide formation as discussed above, also in—
`duces attacks in cluster headache sufferers (43), but,
`as in migraine, only in susceptible individuals and
`after a surprisingly long latency period. This sug—
`gests that,
`in both conditions, NO initiates a slow
`pathological reaction which eventually leads to the
`attack,
`
`Meningitis and encephalitis, which cause severe
`headache, increase the formation of cytokines, which
`again stimulate macrophage inducible NO synthase
`and production of NO (44). Migraine sufferers are
`more sensitive to endotoxin than non—migraineurs
`(45) and endotoxin stimulates the formation of cy—
`tokines. Hypoxia is another known cause of vascular
`headache (46) and, conversely, pure oxygen has
`been used as an effective treatment
`for cluster
`
`causes a more rapid inactivation of NO and thereby
`shortens and diminishes its effect (31). After head
`trauma, headache often occurs with a delay of hours
`or days (46). There is a similar time delay in the
`development of an inflammatory reaction which is
`known to cause an increased formation of NO via
`inducible NO synthase (31, 50). Thus, the vascular
`component of post-traumatic headache may be
`caused by endogenous formation of NO. Ischemic
`cerebrovascular disease is associated with vascular
`
`In approximately 10% of cases,
`headache (46).
`headache occurs before the stroke, so—called sentinel
`headache. During platelet aggregation and thrombus
`formation, a number of substances such as thy-
`droxytryptamine, ADP, ATP, platelet activating fac—
`tor, thrombin and prostacyclin are released. Several
`of these substances stimulate the formation of NO in
`
`headache (47). Hypoxia enhances NO in blood ves—
`sels from several species (48, 49) and hyperoxia
`
`cerebral vascular endothelium (51). Both sentinel
`headache and headache during stroke could therefore
`
`
`
`4
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`

`

` 98
`
`CEPHALALGIA 15 (1995)
`
`J Oiesen et 511.
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`be secondary to thrombus formation and increased
`vascular concentrations of NO.
`
`Support for the second part of the
`hypothesis
`The observation that migraine attacks develop sev—
`eral hours after an NO challenge suggests that NO
`may be involved in the early phase of spontaneous
`migraine attacks. Therefore, drugs which directly
`counteract NO (endothelial receptor blockers, NOS
`inhibitors, nitric oxide scavengers, etc.) may be effec-
`tive in the acute treatment of migraine but are also
`likely to be effective in migraine prophylaxis. Our
`knowledge of NO effects on the cranial circulation
`and perivascular nerves and of NO production in
`human
`cerebrovascular
`endothelium is
`limited.
`
`Therefore when and how existing antimigraine drugs
`interact with the NO triggered cascade of reactions
`leading to migraine remains to be elucidated. Some
`observations do suggest an impOrtance for such
`interactions.
`
`Sumatriptan, the most specific drug for the treat-
`ment of migraine attacks, reduces CTN-induced im-
`mediate headache and in parallel contracts cerebral
`and extracerebral arteries (52.). Thus, sumatriptan
`attenuates NO-induced headache. Because it remains
`
`to be determined how sumatriptan acts in migraine,
`NO antagonism may turn out to be an important
`effect. Pure oxygen has been used successfully in the
`treatment of cluster headache (47) but has not been
`sufficiently studied in migraine. Nitric oxide is re—
`moved from tissues by oxidation to form NO;
`(nitrate) (31). The action of pure oxygen thus may
`be explained by its role as NO scavenger in cerebral
`arteries.
`
`voltage-dependent
`block
`Calcium antagonists
`Ca++ channels, thereby reducing the concentration
`of free cytosolic calcium. Since the constitutive NO
`synthase in the endothelium is Ca++ dependent (14),
`calcium antagonists might exert
`their prophylactic
`effect
`in migraine via decreased activity of NOS.
`Methysergide and pizotifen are 51-iTz antagonists
`which do not discriminate between the 51-1sz and
`the SHTZC receptor. It has recently been suggested
`that
`their effect
`is via 5HT3C receptor antagonism
`(53). The SHTlc (formerly called SHTK) receptor
`stimulation liberates endothelial NO (54). Thus,
`amine antagonists may well exert
`their action by
`reducing endothelial NO production.
`Propranolol blocks isoprenaline—induced relaxation
`of rat
`thoracic aorta in an endothelium—dependent
`fashion. The response is also blocked by the NOS
`inhibitor L—NOARG (55). Similar observations have
`been made in rabbit aorta (56). The prophylactic
`effect of beta-adrenergic blockers in migraine may
`thus be due to their blockade of beta—adrenoceptor
`stimulated NO production. Propranolol also antago—
`
`W..—A
`i"Wit1:“.l l
`
`
`(57), another
`5I-IT3C receptors
`endothelial
`nizes
`mechanism whereby it may reduce endothelial NO
`production.
`In contrast
`to propranolol, pindolol,
`which is ineffective in migraine, lacks affinity for the
`5HT2: receptor (54).
`
`Support for the third part of the hypothesis
`Exogenous NO from CTN may induce migraine as
`described above, but what of other substances which
`reportedly cause headache? In long—term drug stud-
`ies,
`for example,
`the recent study of
`tacrine for
`dementia (58), headache is one of the most common
`adverse events, occurring in 10 and 15% of patients.
`But, headache is equally frequent in placebo groups
`of controlled trials. This high frequency of headache
`apparently reflects a high prevalence of headache in
`the general population. On the other hand, when
`single doses of Substances are studied, the occurrence
`of headache as an adverse event is usually only a few
`percent (59). The only substances which have been
`shown to reliably cause more headache than placebo
`in single—dose experiments are GTN, histamine,
`re—
`serpine, mCPP and,
`less convincingly, prostacyclin
`and hypoxia. Alcohol may trigger migraine in some
`sufferers after a variable period of
`time but
`the
`hangover headache is a complex phenomenon in—
`volving a variable proportion of toxic, abstinence,
`myofacial and psychological mechanisms.
`Histamine is well known to cause headache. In all
`likelihood, the effect is intracranial, because histamine
`injections
`into the internal carotid artery cause
`headache, whereas injections into the external carotid
`artery do not (60). In a controlled trial 24 of 2.5
`migraineurs, 5 of IO tension—type headache sufferers
`but no control
`subjects develOped a pulsating
`headache during intravenous infusion of histamine.
`The headache differed from migraine. It was bilateral,
`of mild to medium severity and without nausea. The
`headache was greatly reduced or abolished by
`mepyramine, a histamine H1 receptor antagonist
`(15). In recent as yet unpublished studies, we con—
`firmed these findings in a double—blind crossover
`design employing continuous intravenous histamine
`infusion. Histamine stimulates endothelial
`l-i1
`re-
`ceptors in vitro and dilates blood vessels, probably
`via formation of NO (2.2, 2.3). Histamine-induced
`headache is therefore possibly mediated by NO. Our
`recent study showed that histamine, given to mi~
`graine sufferers, causes a delayed migraine several
`hours after infusion, exactly as previously described
`for GTN. The similarity of these headache profiles is
`so striking that a common mediator is likely to be
`involved and we suggest this is NO.
`Hypoxia causes headache,
`the best-known exam—
`ple being high—altitude headache. No formal study of
`the effects of hypoxia in migraine sufferers is avail—
`able, however. Recently, Arregui et al. (61) showed
`
`if
`
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`
`CEPHALALGIA 15 (1995)
`
`NO in migraine
`
`99
`
`that persons living at high altitude had a large
`increase in migraine prevalence. Hypoxia prolongs
`the action of NO, whereas pure oxygen acts as a NO
`scavenger,
`thereby shortening the effect of NO.
`Hypoxic vascular headache and hypoxia—induced mi—
`graine therefore may involve the spontaneous pro-
`duction
`of
`increasing NO concentration with
`prolonged action.
`Prostacyclin causes vascular headache in migraine
`sufferers (62.). Prostacyclin is a vasodilator acting
`directly on smooth muscle receptors in cerebral ves—
`sels protected by the bloodubrain barrier; however,
`the action is thought to be via endothelial receptor
`mediated liberation of NO (31).
`In migraine sufferers, reserpine also causes vas—
`cular headache with some migraine features (63).
`Reserpine depletes not only platelets but also presy-
`naptic nerve terminals of their monoamine content,
`including 51-11". The 5HT1C receptor may play a crucial
`role in the initiation of migraine attacks (53) although
`this is controversial. The endothelium-dependent re—
`laxing response of SHT in a number of vascular beds
`of different species is mediated via the 51-i"l"3c receptor.
`The vascular response to SHTZC activation, at least in
`the pig, is primarily a consequence of the release of
`NO (54). The drug mCPP is a direct agonist at the
`5HTZC receptor and, therefore, also may cause vascu-
`lar headache via NO synthesis (53).
`We believe that GTN and histamine, which reliably
`induce vascular headache in non—migraine subjects
`and migraine in migraine sufferers, do so by activating
`the NO—CGMP pathway. Headache induced by other
`substances such as reserpine, mCPP and prostacyclin
`as well as by hypoxia have been studied less well in
`regard to headache characteristics and mechanisms.
`For each agent, however, there is at least one known
`mechanism whereby the NO—CGMP pathway could
`be stimulated. Whether this is the only or the major
`mechanism of the headache remains to be determined.
`
`As more substances with headache—inducing proper—
`ties are studied, it may become clear if our hypothesis
`can explain all experimental vascular headaches or
`whether other mechanisms apply.
`
`Conclusions
`
`We hypothesize that NO is a triggering molecule for
`migraine attacks. Drugs which treat acute attacks as
`well as prevent migraine appear to block the NO—
`cGIVIP pathway and drugs known to induce migraine
`attacks or vascular headache may do so by stimulating
`the NO—cGMP pathway. With increasing knowledge
`of NO and its physiological and pathophysiological
`actions, tools for the further elucidation of our hy-
`pothesis are becoming available rapidly. Highly selec—
`tive drugs which stimulate or inhibit the NOHCGMP
`pathway at different
`levels are currently available,
`
`although only a few are in clinical trials as yet, and
`will provide the opportunity to address our hypoth-
`esis in greater depth. We believe that an understand—
`ing of the action of NO will have major impact upon
`future research into the pathogenesis of migraine and
`upon the development of new treatments.
`
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`40.
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`41.
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`42.
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`43.
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`44.
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`45.
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`46.
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`47.
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`48.
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`49.
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`50.
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`51.
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`52..
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`5.3.
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`55.
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`56.
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`57.
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`58.
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`59.
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`60.
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`61.
`
`(32..
`
`63.
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`
`
`
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`INSTRUCTIONS TO AUTHORS
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