Special Article

Melatonins Role as an Anticonvulsant

and Neuronal Protector:
Experimental and Clinical Evidence
Muñoz-Hoyos; Miguel Sánchez-Forte; Antonio Molina-Carballo; Germaine Escames;
Encarnación Martin-Medina; Russel J. Reiter; Juan A. Molina-Font; Darío Acuña-Castroviejo

Antonio

ABSTRACT

pineal gland classically has been considered as a vestigial and mystic organ. In the last decades, and with the incorporation of new methodologic procedures, it could be proved that it also has physiologic actions that vary depending on
the level of the phylogenetic scale. Its best-known secretion, melatonin, has been related to many different actions, such
as sleep promotion, control of biologic rhythms, hormonal inhibition, and an inhibiting action on central nervous system
regulation mechanisms. In animal experimentation, there are papers even accepting an anticonvulsant effect. In humans,
evidence is reduced to few experiences. In addition to this clinical experience, there is other evidence that clearly relates
melatonin to convulsive phenomena. This relationship must be mediated by the following mechanisms attributed to melatonin: altered brain GABAergic neurotransmission, its known interaction with benzodiazepinic brain receptors, through
tryptophan metabolite activity (kynurenine, kynurenic acid), or even by its efficacy as a free-radical scavenger. (
J Child
1998;13:501-509).
Neurol
The

A number of biologic processes exhibit a 24-hour periodicity

and are thus referred to as circadian The control of these
biologic rhythms seems to depend on the suprachiasmatic
nucleus in mammals.2 In most species, an important signal
responsible for determining the 24-hour rhythmicity of the
suprachiasmatic nucleus is the light/dark cycle.3 Since the
suprachiasmatic nucleus is neurally connected to the pineal
gland, the light/dark cycle also regulates the biosynthesis of
the chief secretory product of the organ, ie, melatonin.44
Melatonin is an indolamine synthesized by the pineal gland
from tryptophan. By means of its hydroxylation and decar-

boxylation, tryptophan is metabolized to serotonin, which,

in turn, produces melatonin. The enzyme N-acetyl-transferase, which enzymatically generates N-acetylserotonin
from serotonin, is the limiting step in this metabolic pathway. Thereafter, the O-methylation of N-acetylserotonin
catalyzed by the hydroxyindole-O-methyl transferase produces N-acetyl-5-methoxytryptamine (melatonin). Melatonin is the terminal product in this metabolic pathway
(Figure 1).5 Once produced, melatonin is quickly released
into the circulatory system.o Thus, the alterations in the
synthesis of melatonin are quickly reflected in plasma levels of this product 7; melatonin is produced in a distinctly circadian manner with peak levels occurring at night.g~9 The
rhythm seems to be of importance for at least some of melatonins actions. 10

Received Nov 30, 1997. Accepted for publication Jan

28, 1998.
From the Departamento de Pediatria, Universidad de Granada, España (Drs
Muñoz-Hoyos, Sánchez-Forte, Molina-Carballo, Martin-Medina, and MolinaFont); Department of Cellular and Structural Biology, the University of
Texas Health Science Center, San Antonio, TX (Dr Reiter), and the
Departamento de Fisiologia, Instituto de Biotecnologia, Universidad de
Granada, España (Drs Escames and Acuña-Castroviejo).
Address correspondence to Dr A Munoz-Hoyos, Departamento de Pediatria,
Facultad de Medicina, Avda de Madrid 12, E-18071 Granada, Spain.

RELATIONSHIP BETWEEN THE

PINEAL GLAND AND CONVULSIONS
Circadian

Aspects

of Seizures

It is known that many epileptic patients show periodicity in

the occurrence of their seizures. 11 1 More than 60% of seizures
are temporally associated with the period of sleep.2 This
coincidence between seizures and sleep is reflected in
electroencephalogram (EEG) alterations produced during
501

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502

Figure

1. Metabolic

degradation of tryptophan

to

methoxyindole pathway (vg: melatonin)

sleep or at the moment of awakening, and may be caused

by changes in the convulsive sensitivity over a 24-hour
periods. 12 By monitoring the EEG,13 it was possible to correlate the EEG periodicity with the convulsive sensitivity. 14,15 While it remains unknown, the changing sensitivity
to convulsions may relate to the central rhythm generator,
the suprachiasmatic nucleus, and to the rhythmic secretion of melatonin by the pineal glad. 11 A substantial amount
of new evidence suggests an involvement of the suprachiasmatic nucleus and the pineal gland in convulsive pathology : (1) rats display a different sensitivity to audiogenic
seizures depending on the time of the day at which they are
exposed to the stimulus; (2) the photosensitive mandril
exhibits a circadian rhythm in the sensitivity to seizures that
parallels the cortisol rhythm a rhythm also regulated by
the suprachiasmatic nucleus and influenced by melatonin;
(3) the rhythm in the peak-wave complexes of the rat EEG
depends on the light/dark cycle 18; (4) melatonin seems to
modify the circadian nature of the both ketamine-induced

and

kynurenine pathway.

catalepsy and y-hydroxybutyrate-induced absences in chickensl9; (5) unusual light pulses or the exposure to a different
light/dark cycle may induce seizures in some epileptic
patients20,21; changes in the light/dark cycle also affect seizure
activity in the photosensitive baboon (Papio papio),22 and
the cat; (6) continuous exposure to light eliminates the
rhythm of convulsive sensitivity in the mandril, which is
observed normally when the animal is maintained under a
12-hour light/dark cycle; typical mandrils under continuous
light exhibit an increase in convulsive sensitivity compared
to those under a 12-hour light/dark cycle; (7) the seasonally
dependent changes in the photoperiod (increasing or
decreasing the number of light hours) seems to be related
to temporal changes in convulsive activity.23,24 The existence
of

seasonal and/or lunar component in both human

epilepsy24 and experimental epilepsy in animals25 has been

proposed. Several studies suggest that humans are more
likely to experience seizures during summer. Finally, seasonal
rhythm in the sensitivity to electroshock-induced seizures

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503

has been correlated with the seasonal

~y-aminobutyric acid (GABA) levels

depression in brain

Evidence From Animal Experiments

There are four main experimental models of epilepsy:
(1) epilepsy in animals that exhibit an increased genetic susceptibility to seizures; (2) seizures induced by the application of electric discharges, ie, electroshock; (3) seizures
induced by proconvulsant drugs; and (4) seizures caused by
pineal gland removal, which either directly causes seizures
or increases the animals sensitivity to seizure-provoking
stimuli. Thus, in pinealectomized rabbits, contralateral hippocampal stimulation induces a pattern of EEG recording
with convulsive characteristics in the opposite hippocampus.27 Similarly, pinealectomy increases the likelihood that
these animals will exhibit seizures Likewise, the
intracerebroventricular injection of antimelatonin antibody
induces paroxysmal neural discharges, suggesting that mela-

tonin may normally act as an endogenous agent inhibiting

the electrical activity of the brain.z9 Also, the in vitro application of melatonin to cultured guinea pig hippocampal
neurons produces an inhibition of the neuronal excitability.3
Rats are seemingly more resistant to pinealectomy-induced
seizures and show only convulsive-like cortical paroxysmal
neuronal discharges when the pineal gland is removed.31
However, when the gland is surgically removed from parathyroidectomized rats, 80% of the animals develop violent
seizures28,31 and often die. In gerbils (Meriones unguiculatus), pinealectomy alone induces convulsions.32
While the administration of crude pineal extracts
is unable to counteract induced seizures in either rats or
gerbils, subcutaneous implants of melatonin reduce the
convulsive tendency of gerbils but not rats.31-33 In pinealectomized gerbils, a decrease in the production of cortical

norepinephrine could be responsible for the increased conactivity exhibited by these animals. Likewise, in
parathyroidectomized, pinealectomized rats, depressed norepinephrine levels may also relate to their increased susceptibility to seizures.33 Interestingly, in experiments
conducted using gerbils, pinealectomy during the summer
led to much more severe seizures than if the surgical procedure was performed in the winter. 32,34
Administration of pineal extracts causes a generalized
desynchronization of the electroencephalogram, increasing
vulsive

the convulsive threshold for the cortical electrical stimulation in the isolated cat brain.35 The ability of melatonin to
reduce the stimulatory effects of amphetamines revealed the
sedative and anticonvulsant roles of the indolamine. In
chickens, melatonin-induced sleep shows EEG slow-wave
characteristics similar to those typical of normal sleep. In
these animals, pinealectomy desynchronizes the EEG, an
effect counteracted by melatonin administration.36 Melatonin
also has a tranquilizing effect when administered to the
photosensitive baboon. This effect of melatonin seems to
depend on a reduction in the light sensitivity of the animals,
followed by an increase in the latency to seizure onset. 17

The anticonvulsant potential of melatonin was tested

successfully in several types of experimental convulsions,
including those induced by pentylenetetrazole and electrical stimulation of the amygdala.3s Melatonin is a highly
effective anticonvulsant in seizures induced by pentylenetetrazole injection and less so in the case of convulsions
caused by electrical stimulation of the amygdala. At melatonin doses that do not produce sedation, the indolamine
also reduces duration and number of after discharges. Using
melatonin doses that cause mild sedation, the indole
decreases the intensity of convulsions. These experiments
suggest that melatonin has significant anticonvulsant properties, although to a lesser extent than barbiturates, benzodiazepines, or valproic acid.3s Valproic acid and
benzodiazepines increase brain GABA content, which is
believed to explain the anticonvulsant activity of these
drugs. Melatonin seems to yield a biphasic response in
terms of brain GABA concentrations; thus low doses of the
indolamine increase brain GABA concentrations, whereas
high doses of this compound decrease them
Evidence From Clinical Experience
There are few studies in relation to the anticonvulsant

potential of melatonin in humans. As mentioned above,

epileptic convulsions have been found to exhibit a circadian
rhythm.37 A shift of the normal sleep/wake cycle, stress,
alcohol consumption, and pregnancy 38,39 may increase
convulsive frequency. Since melatonin is often considered
an antistress hormone with anticonvulsant properties, this
pineal constituent may be useful in the therapy of convulsive pathology. Doses above 2 g per day reduced peak activity and convulsive frequency in patients with intractable
temporal lobe epilepsy.4o,41 Peak activity in these patients
was changed by slow theta waves in the hippocampus and
temporal cortex after melatonin administration. Other neurologic diseases were also improved after melatonin treatment. 40,41 In epileptic children, continuous infusion of
melatonin decreases electrocortical activity, whereas an
increase in electrical activity was found 30 minutes after infusion

was

concluded.42

In experimental animals, melatonin administration

induces sedation and sleep.43,44 In humans, melatonin induces
sedation, hypnosis, and a feeling of well being, and decreases
electrocortical activity.4 1>45-47 Melatonin is currently used in
the treatment of sleep disturbances, jetlag, and seasonal
affective disorders.48,49 In Parkinsons disease, continuous
administration of melatonin significantly reduces tremor. 50

Moreover, parkinsonian patients experience an improvement

in daily task performance.45 An inverse relationship between
serum and urinary melatonin levels and depressive symptoms have also been shown.51,52 In animal models, it has been
found that melatonin decreases neuronal excitability and acts
as a natural anticonvulsant. 25,29,30,36,53 Alterations in the circadian rhythm of epileptic convulsions in children and the
disappearance of the melatonin rhythm in children with
febrile seizures has been reported (Figure 2). .7~1,55 Following

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504

Melatonin levels during, after 60 minutes, and after 24

convulsive episode in children. A significant decrease
(~, P< .001) of melatonin production is seen after only 60 minutes of
a convulsive episode.
3.
hours of

Figure

Figure 2. Different patterns of melatonin secretion between normal

children (a) and children with febrile (b) or epileptic (c) seizures. In children with febrile seizures, the normal rhythm of melatonin secretion
disappears.

the seizures, the children showed an increase in plasma

melatonin levels.56,57 A linear correlation between plasma levels of melatonin and the duration of a convulsion was also
reported. These data suggest a role for melatonin in the modulation of brain excitability and participation in the development of the refractory postictal period. 57 Recently, an
increase in plasma melatonin after 60-minute seizures, with
a normalization of these levels 24 hours later, was also
reported in children (Figure 3).58
Taking into account the experimental and clinical data
regarding melatonin as a potential anticonvulsant, we instituted its use in the treatment of an epileptic child. At the age

of 1 year, the girl was diagnosed with progressive myoclonic

epilepsy. As in the majority of the cases, anticonvulsant
therapy was not effective. The child displayed 15 to 20
seizures per day at the age of 24 months. At that time, melatonin was added to the treatment (100 mg every 12 hours).
This melatonin schedule resulted in obvious sleep/wake
disturbances with diurnal somnolence; thereafter the
sleep/wake cycle was normalized by giving 20 mg melatonin at 9 AM and 100 mg at 9 PM. Melatonin administration
significantly reduced the frequency and intensity of the
seizures. After 30 months of melatonin treatment, the child
was essentially devoid of seizures. The Spanish Ministry of
Health subsequently prohibited the use of melatonin in
humans and the treatment was discontinued. One month
later, the intensity and frequency of seizures increased in the
child.59 Similar experiences with other types of infantile
epilepsy also have been reported. 60
The anticonvulsant role of melatonin described here
probably relates to the multiple actions of this molecule in
the brain. These actions include: (1) a potentiation of the
brains inhibitory neurotransmission, (2) the inhibition of the
brains excitatory neurotransmission, primarily by altering
GABA neurotransmission, (3) the antioxidant activity of
the indolamine, and (4) the regulation of several enzymes
involved in free radical metabolism. A close relationship

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505

between brain tryptophan methoxyindole metabolites (melatonin in particular) and brain tryptophan kynurenine metabolites (with important pro- and anticonvulsant properties) has
been reported.61 This relationship does not occur in children
with convulsions (Figure 4).
MELATONIN MECHANISM OF ACTION

Changes in the circadian system and therefore alterations

of biologic rhythms may be the basis for some neural alterations, such as excitability. Properly timed melatonin administration may resynchronize altered circadian rhythms,
thereby normalizing neuronal excitability. 62
Long-term administration of melatonin induces an
increase in GABA affinity in rat brain, without changes in
the number of its receptors.63 The authors suggest that the
psychopharmacologic effects of melatonin are, in part,
related to the changes in GABA neurotransmission. GABA
is the main inhibitory neurotransmitter in the mammalian
brain. The GABAA receptor is a macromolecular complex
including (in the simplest form) two alpha and two beta subunits. Beta subunits are the locus for GABA binding (and
GABA agonists and antagonists), whereas alpha subunits
possess the receptors for GABA modulators such as benzodiazepines, barbiturates, and other anticonvulsant drugs
It is known that GABAA and benzodiazepine receptors
exhibit a circadian rhythm in the cerebral cortex of rats; these
rhythms depend on the existence of an intact pineal gland.
Pinealectomy, which eliminates the 24-hour melatonin
rhythm, blunts the benzodiazepine cycle and increases the
number of GABA receptors at night. 65,66 Melatonin administration at near physiologic doses (50 /-1g!kg IP) counteracts
the effects of pinealectomy, suggesting a role for indolamine
in the control of the GABAA benzodiazepine receptor complex.65,66 Additionally, melatonin administration also
increases GABA and serotonin levels in the brain. Conversely, anticonvulsant drugs typically affect pineal gland
indole metabolism.67,68 The effects of melatonin on the
GABAA receptor are not due to its direct actions on the
GABAA and benzodiazepine receptors themselves. 65, 116 High
affmity ouabain receptors in the Na+, KI-ATPase in rat-brain
cerebral cortex has been observed .69 This receptor, displaying a circadian rhythm that peaks at night,7 is under
pineal control. Melatonin administration increases the affmity of ouabain for its receptor. 70 Melatonin, by altering
sodium pump activity, may change membrane permeability
to

some

ions, thereby changing

GABA A-benzodiazepine

receptor complex activity. Melatonin also modifies benzodiazepine receptors by potentiating the effects of corticotropic1 and opioid peptides.72,73 As a result, melatonin
potentiates GABAergic neurotransmission, which probably explains, at least in part, the hyperpolarizing and anticonvulsant effect of the indole. 36,37,73,74 Stimulation of the
GABAA receptor produces an inhibitory response caused by
hyperpolarization by Cl- influx into the cell. However, highintensity GABAA stimulation produces an excitatory
response: bicarbonate ion effluxes occur to compensate

4. Disappearance of the correlations between melatonin and

kynurenine pathways after a convulsive episode in children, at night
(21:00-09:00 h). In the control group, a normal (significant) increase
in melatonin production occurs during the night concomitantly with
a significant decrease in the urinary excretion of kynurenine metabolite, whereas the inverse pattern occurs during the day (data not
shown). In the convulsive groups, a higher increase of the nocturnal
production of melatonin is seen, whereas the production of 3HK,
KYNA, and XA also increased. Similar changes occur during the diurnal period (09:00-21:00 h), data not shown. NCG: night control group;
NFG: night febrile group; NEG: night epileptic group; aMTS: serum
melatonin; aMT-0: urine melatonin; L-kyn: L-kynurenin; 3HO-K;
3-OH-kynurenin; KA: kynurenic acid; XA: xanthurenic acid; 3HO-AA:
3-OH-anthranilic acid. # P< .01 vs NCG, P< .001 vs NCG.

Figure

for Cl- influx This dual role of GABAergic neurons may

explain the proconvulsant effect of high doses of

melatonin. 59,76
Melatonin is metabolized to kynurenines in the brain. 77

Kynurenine and its metabolite, kynurenic acid,

seem

to be

related to convulsive activity.&dquo; Kynurenine administration

is proconvulsant, 77 whereas kynurenic acid inhibits seizure
activity in rats8l and inhibits audiogenic convulsions in
mice.gz The inhibitory action of kynurenic acid seems to
depend on its antagonism of excitatory amino acid neurotransmission in the brain.83,84 It is documented that hormonal changes and seizures are often related.85 Kynurenine
production from tryptophan changes depending on the
phase of the menstrual cycle,86 which modifies central levels of kynurenine as well as convulsive sensitivity. A correlation between seizures and stages of the menstrual cycle
is known to exist, and hormonal contraceptives may
decrease seizures.87 Peripheral kynurenine production from
tryptophan depends on the stage of the ovarian cycle. 86

Conversely, seizures may modify certain hormonal patterns;

specifically the levels of prolactin and cortisol. 88-90 Seasonal-dependent changes in hormonal levels are often
related to changing pineal physiology.9
Besides potentiating brain inhibitory neurotransmission through GABAA-benzodiazepine receptor complex
modulation, melatonin also inhibits brain excitatory neurotransmission. Extracellular unit recordings have shown
that the iontophoretic application of melatonin inhibits
either or both basal and evoked neuronal discharges in the
rat striatum.74,92 The effect of melatonin is related to

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dopamine D1 and Dz receptors present on the striatal units.92

In other sets of experiments, rat striatal neuron activity
was evoked by motor cortex stimulation. The cortico-striatal pathway is glutamatergic with the released glutamate
acting on both ionotropic and metabotropic receptors.
Ionotropic glutamatergic receptors are classified as
N-methyl-D-aspartate (NMDA) and non-NMDA receptors
(the latter receptors included a-amino-3-hydroxy-5-

methylisoxazole-4-propionic acid [AMPA]-kainate and

quisqualate subtypes). Iontophoretically applied melatonin
specifically inhibits the excitatory response elicited in striatal neurons after motor cortex simulation. 12 The inhibitory
effect of melatonin is similar when either glutamate or
NMDA are iontophoretically applied to striatal neurons.
Melatonin does not inhibit, however, the excitatory response
induced by the iontophoresis of AMPA-hydrobromide on rat
striatal neurons. These data suggest that melatonin specifically inhibits the NMDA subtype of glutamatergic receptors
in rat striatum,3 although the specific mechanism of action
of melatonin remains known. Several data suggest the
involvement of calcium ions in the effects of melatonin,
and it seems that the indole acts as an antagonist of L-type
calcium channels.94 Melatonins inhibitory effect on the
NMDA receptor does not occur when A-23187, a calcium
ionophore, is applied simultaneously with the indolamine.
Moreover, melatonin potentiates the inhibitory response
to the iontophoretic ejection of w-conotoxin-GVIA?4 From
these data, the possibility arises that the inhibitory role of
melatonin on neurons may depend on its antagonism of
calcium influx into the neuron.
Interestingly, when melatonin is iontophoretically
applied to striatal neurons, the inhibitory effect on NMDA
excitation appears 2 to 4 minutes after its ejection. ~12 This
is a long latency for iontophoretic experiments, and it suggests that melatonin does not act on a hypothetical membrane receptor. Thus, the possibility of an intracellular
action for melatonin arises. In fact, melatonin displays highaffinity binding for calcium-calmodulin95 and thus melatonin blocks the calcium-calmodulin-dependent effects on
cells. One of these effects is the activation of the constitutive nitric oxide (NO) synthase activity, the enzyme responsible for NO synthesis. Several reports show an inhibitory
role for melatonin on NO synthase activity at physiologic concentrations.96 The consequence of NMDA activation is an
increased calcium influx, which activates NO synthase and
thus NO production,97 which is responsible for the NMDA
excitatory response.97 As a result of melatonin iontophoresis on striatal neurons, two main effects related to calcium
metabolism are seen to occur: (1) the decrease in calcium
influx into the neuron, thereby decreasing the formation of
calcium-calmodulin complexes, and (2) because of its
lipophylicity, melatonin enters into the cell and binds to calcium-calmodulin, inactivating this complex. Thus, the result
of melatonins action is to reduce NO production by the neuron. This may explain the long latency for the effect of
melatonin after iontophoresis and its specific inhibition of
the NMDA receptor excitability. The anticonvulsant role of

melatonin may partially depend on its ability to inhibit the

NMDA receptor, and reflects the antiexcitotoxic role of the
indolamine.
Other biochemical and electrophysiologic experiments
suggest that the anticonvulsant activity of melatonin may also
depend on its antioxidant activity, since it is known to be a
scavenger of free radicals.98-100 Free radicals are highly reactive molecules because of the presence of a non-paired electron. Free radicals are produced from oxygen during cellular
metabolism with the hydroxyl radical (OH) being the most
reactive radical generated in cells. Excessive stimulation of
NMDA and kainate receptors may induce cell death by excitotoxic mechanisms involving NO,101,102 itself a radical.
Although NO is considered a neuronal mediator in the brain,
NO also reacts with the superoxide anion radical (produced
during activation of the kainate receptor) leading to the formation of peroxynitrite and eventually an OH-like radical.
These radicals induce lipid peroxidation and cell death. 103
Under normal conditions, free radicals are neutralized by
endogenous antioxidants, including melatonin. 104 However,
an abnormal stimulation of NMDA and kainate receptors,
which seems to occur during epileptic convulsions, produces an excess of free radicals, reducing endogenous antioxidants. The result is a higher concentration of free radicals,
which in turn increases lipid peroxidation and neuronal
death. Melatonin not only counteracts the effects of oxygen
radicals produced during excitotoxicity, but also reduces NO
synthase activity. 93, 105, 106 In vitro and in vivo studies have
demonstrated the potency of melatonin as a scavenger of *OH
and as an inhibitor of lipid peroxidation; there is some evidence that melatonin is a better scavenger than either glutathione or vitamin E. 17-19 A large amount of evidence is now
available supporting the antioxidant role for melatonin as well
as its neuroprotective function.o~,l02,llo-llz
Despite these considerations regarding melatonin as an
important component of the endogenous antioxidant system, it is difficult to define the usefulness of melatonin as
an anticonvulsant in the clinical situation for several reasons:
(1) lack of specific studies of melatonins effect on epilepsy
in humans, (2) lack of information concerning effective
doses, and (3) possibility of unknown side effects. With the
rapid accumulation of knowledge concerning melatonin in
recent years, it is possible that information will be available
soon concerning melatonins efficacy and safety. Certainly,
searching for an anticonvulsant drug that acts on the NMDA
receptor, without negative side effects, is a goal of several
research laboratories. In this connection, we feel that the
potential of melatonin (or a melatonin analog) in this regard
should be examined carefully. Melatonins ability to alter
GABAergic neurotransmission, its inhibition of glutamatergic
neurotransmission, its antiexcitotoxic properties, and its lack
(to date) of negative collateral effects, supports the continued
investigation of melatonin, alone or in combination with
other drugs, as a promising anticonvulsant drug. Some clinical evidence already shows that melatonin may be useful
as a treatment because of its ability to modulate endogenous
systems, which modify the convulsive threshold.

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