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Melatonin in septic shock: Some recent concepts
☆
Venkataramanujan Srinivasan PhD
a
, Seithikurippu R. Pandi-Perumal MSc
b
,
D. Warren Spence BA
c
, Hisanori Kato PhD
d
, Daniel P. Cardinali MD PhD
e,
⁎
a
Sri Sathya Sai Medical Educational and Research Foundation, Prsanthi Nilayam, Plot-40 Kovai Thirunagar,
Coimbatore-641014, India
b
Somnogen Inc, New York, NY 11418, USA
c
Canadian Sleep Institute, Toronto, ON, Canada M3H 3V6
d
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo,
Bunkyo-ku, Tokyo 113-8657, Japan
e
Departmento de Docencia e Investigación, Facultad de Ciencias Médicas, Pontificia Universidad Católica Argentina,
C1107AFD Buenos Aires, Argentina
Keywords:
Melatonin;
Septic shock;
Antioxidants;
Cytokines;
Nitric oxide
Abstract Melatonin is a versatile molecule, synthesized not only in the pineal gland, but also in many
other organs. Melatonin plays an important physiologic role in sleep and circadian rhythm regulation,
immunoregulation, antioxidant and mitochondrial-protective functions, reproductive control, and
regulation of mood. Melatonin has also been reported as effective in combating various bacterial and
viral infections. Melatonin is an effective anti-inflammatory agent in various animal models of
inflammation and sepsis, and its anti-inflammatory action has been attributed to inhibition of nitric oxide
synthase with consequent reduction of peroxynitrite formation, to the stimulation of various antioxidant
enzymes thus contributing to enhance the antioxidant defense, and to protective effects on mitochondrial
function and in preventing apoptosis. In a number of animal models of septic shock, as well as in
patients with septic disease, melatonin reportedly exerts beneficial effects to arrest cellular damage and
multiorgan failure. The significance of these actions in septic shock and its potential usefulness in the
treatment of multiorgan failure are discussed.
© 2010 Elsevier Inc. All rights reserved.
1. Introduction
Melatonin is a major secretory product of the pineal gland
released every day at night. In all mammals, circulating
melatonin is synthesized primarily in the pineal gland. In
addition, melatonin is also locally found in various cells,
tissues, and organs including lymphocytes, human and murine
bone marrow, the thymus, the gastrointestinal tract, skin, and
the eyes where it plays either an autocrine or paracrine role
[1,2]. Both in animals and in human beings, melatonin
participates in diverse physiologic functions, not only signaling
☆
Disclosure: SR Pandi-Perumal is a stockholder and the President and
Chief Executive Office of Somnogen Inc, a New York corporation. He
declared no competing interests that might be perceived to influence the
content of this article. All remaining authors declare that they have no
proprietary, financial, professional, or any other personal interest of any
nature or kind in any product or services and/or company that could be
construed or considered a potential conflict of interest that might have
influenced the views expressed in this manuscript.
⁎Corresponding author. Faculty of Medical Sciences, Department of
Teaching & Research, Pontificia Universidad Católica Argentina, 1107
Buenos Aires, Argentina. Tel.: +54 11 43490200x2310.
E-mail addresses: danielcardinali@uca.edu.ar,
danielcardinali@fibertel.com.ar (D.P. Cardinali).
0883-9441/$ –see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.jcrc.2010.03.006
Journal of Critical Care (2010) 25, 656.e1–656.e6
the length of the night (and thus the time of the day or the season
of the year) but also enhancing free radical scavenging, the
immune response, and cytoprotective processes.
In several animal models, melatonin has been identified to
protect against bacterial, viral, and parasitic infections
presumably by acting through a variety of mechanisms, like
immunomodulation or direct or indirect antioxidant activity
[3]. Melatonin is a powerful antioxidant that scavenges
superoxide radicals as well as other radical oxygen species
(ROS) and radical nitrogen species and that gives rise to a
cascade of metabolites that share its antioxidant properties.
Melatonin also acts indirectly to promote gene expression of
antioxidant enzymes and to inhibit gene expression of
prooxidant enzymes [2].
Septic shock, the most severe problem of sepsis, is a lethal
condition caused by a pathogen-induced long chain of
sequential intracellular events occurring in immune cells,
epithelium, endothelium, and the neuroendocrine system [4].
The lethal effects of septic shock are associated with the
production and release of numerous proinflammatory
biochemical mediators like cytokines, nitric oxide (NO),
ROS, and radical nitrogen species radicals, together with
development of massive apoptosis.
Melatonin has been shown to be beneficial for reversing
symptoms of septic shock [5]. Melatonin had significant anti-
inflammatory properties presumably by decreasing the
synthesis of proinflammatory cytokines like tumor necrosis
factor (TNF)–αand by suppressing inducible NO synthase
(iNOS) gene expression. Melatonin also exerts a strong
antiapototic effect [2]. This review article is focused on the
significance of melatonin in septic shock and its potential
utility to treat multiorgan failure. Published studies on animal
models of inflammation and sepsis are summarized in
Supplemental Tables 1 and 2.
In the next sections, we will review some of those studies
with the aim of exemplifying the potential therapeutic use of
melatonin in inflammation and septic shock.
2. Melatonin in lipopolysaccharide-induced
inflammation
The first evidence for melatonin in controlling lipopoly-
saccharide (LPS)-induced damage was provided by Sew-
erynek and coworkers [6] in rats. They reported a reduction
in LPS-induced oxidative insult after melatonin administra-
tion, as evidenced by decreased hepatic malondialdehyde
(MDA) and 4-hydroxyalkenal (4-HDA) [6].
Melatonin prevents LPS-induced endotoxemia presum-
ably by reducing circulating TNF-αlevels, superoxide
production in the aorta, and iNOS in the liver [7].
Melatonin (10-60 mg/kg) administered intraperitoneally
(IP) to rats before and/or after LPS significantly decreased
lung lipid peroxidation and counteracted the LPS-induced
increase of NO levels in lungs and liver in a dose-
dependent manner [8]. It also prevented LPS-induced
metabolic alterations.
The activation of mitochondrial NOS can be a crucial
trigger for initiation of the chain of events leading to septic
shock [9]. The mitochondria express constitutive and
inducible forms of NOS, the latter causing mitochondrial
respiratory inhibition and failure. The protective role of
melatonin against the enhancing effects of LPS on
mitochondrial iNOS and the activity of respiratory com-
plexes in liver and lung mitochondria were evaluated in
young and old rats [10]. Melatonin administration (60 mg/kg,
IP) effectively counteracted LPS-induced inhibition of
complexes I and IV of the electron transport chain and
decreased mitochondrial NOS activity and NO production,
thereby preventing LPS toxicity [10]. The survival rate of
LPS-injected mice improved from 0% in controls to 48% and
86% after melatonin administration (2 mg/kg) 3 and 6h later,
respectively [11].
The effect of melatonin in preventing septic shock is
complex. Apart from acting on the local sites of inflamma-
tion, melatonin also exerts its beneficial actions through a
multifactorial pathway including its effects as immunomod-
ulator, antioxidant, and antiapoptotic agent. This is exem-
plified by the study performed by Carrillo-Vico et al [12] in
mice. It was reported that IP administered melatonin (10 mg/
kg) 30 minutes before and 1 hour after LPS injection
markedly protected the mice from the lethal effects of LPS
with 90% survival rates for melatonin vs 20% in LPS-
injected mice after 72 hours. Lipopolysaccharide induced the
increase of nitrite/nitrate and lipid peroxidation levels in
brain and liver. Melatonin administration increased the levels
of the anti-inflammatory cytokine interleukin (IL)-10 and
decreased the concentration of proinflammatory mediators
like TNF-α, IL-12, and interferon-γin the local site of LPS
injection [12]. Morphologic evaluation of the apoptotic
process showed that melatonin decreased the LPS-induced
programmed cell death in spleen [12]. Melatonin's anti-
apoptotic action was attributed to its stimulatory effect on IL-
10 levels because IL-10 antiapoptotic action had already
been demonstrated.
The effect of senescence on LPS-induced multiorgan
failure and the efficacy of melatonin treatment to modify this
condition were evaluated in rats [13]. Inducible NOS
expression and activity, nitrite content, lipoperoxidation
levels, and serum markers of liver, renal, and metabolic
dysfunction were measured. An age-dependent increase in
iNOS activity, NO content, and lipoperoxidation levels was
observed; and these changes were augmented further by LPS
[13]. Melatonin decreased the expression and activity of
iNOS, reducing NO and lipoperoxidation levels to basal
values in both LPS-treated groups. Liver, kidney, and
metabolic dysfunctions were also significantly higher in
aged rats and further increased by LPS. Melatonin treatment
counteracted all these alterations in young and aged rats [13].
These findings are significant because the susceptibility of
elderly patients to septic shock and multiorgan failure is
656.e2 V. Srinivasan et al.
much greater than in young individuals. The alteration of the
sleep/wake cycle may be one of the factors explaining this
susceptibility in old individuals. Relevant to this, melatonin
(5 mg/kg IP) attenuated the alveolar damage caused by
LPS and counteracted the reduced levels of Bcl-XL and
procaspase-3 seen in sleep-deprived mice [14]. Melatonin also
prevented the increase of cell death and reduced the elevated
higher levels of MDA in lungs of sleep-deprived mice [14].
It is well known that, during sepsis, ileus and mucosal cell
barrier dysfunction occurs as one of its most frequent
complications. Ileus, by promoting intestinal stasis, bacterial
overgrowth, and bacterial translocation, may cause second-
ary infections and multiple organ failure. By using the LPS
model, the beneficial effects of melatonin in preventing
gastrointestinal disturbances were studied in mice [15]. Mice
treated with LPS exhibited reduced gastric emptying of solid
beads and altered distribution of glass beads throughout the
gastrointestinal tract. Melatonin (10 mg/kg IP) reversed LPS-
induced motility disturbances. Melatonin also normalized the
altered lipid peroxidation, p38 mitogen-activated protein
kinase activation, nuclear factor–κB activation, iNOS
transcription and expression, and nitrite production in
intestinal tissue from septic mice [15]. Melatonin is thus a
molecule with therapeutic potential for the treatment of
systemic inflammation because it interferes at the earliest
step of activation of the oxidative and proinflammatory
cascade. Melatonin and its metabolites may function as
modulatory agents during the inflammatory process and have
the potential to be a new class of anti-inflammatory agents
with specificity for cyclooxygenase-2 and iNOS enzymes
[16]. Melatonin treatment also reduced myeloperoxidase
activity and MDA levels [17].
The possible protective effect of melatonin in LPS-
induced pulmonary inflammation and lung injury was
evaluated in rats [18]. Melatonin (10 mg/kg, IP) given 30
minutes before LPS prevented the decrease in PaO
2
and the
lung injury caused by the endotoxin. Melatonin decreased
pulmonary edema, the elevated lung myeloperoxidase
(MPO) activity, and lipid peroxidation after LPS. The
increase of the proinflammatory cytokine TNF-αlevels in
pulmonary tissue given by LPS was also prevented by
melatonin, whereas the levels of the anti-inflammatory
cytokine IL-10 were augmented. The decrease in LPS-
induced pulmonary edema, lipid peroxidation, and the
infiltration of neutrophils in lung tissue was interpreted in
terms of the TNF-αinhibition and IL-10 stimulation brought
about by melatonin [18].
Severe infection in diabetic patients often leads to
multiorgan failure. In a study conducted to assess the
protective effects of melatonin in LPS-injected rats turned
diabetic by streptozotocin administration, LPS significantly
increased the serum levels of TNF-αand IL-6 in normal and
diabetic rats and augmented plasma corticotropin-releasing
hormone, ACTH, and corticosterone [19]. Both 0.1- and
1-mg/kg melatonin doses significantly decreased serum
levels of TNF-αand IL-6 in LPS-treated rats. Significant
inhibitory effects of melatonin (1 mg/kg) were also
observed on the hypothalamic-pituitary-adrenal axis [19].
Previous studies in diabetic rats indicated that melatonin
was effective to restore normal vascular responses [20].
Therefore, melatonin treatment may help to prevent the
vicious cycle of hyperglycemia and stress factors such as
severe infection in diabetic patients.
3. Melatonin in non-LPS animals models of
septic shock
Short-term melatonin administration (10 mg/kg IP) after
hemorrhage significantly improved survival in animals
subjected to a subsequent septic challenge by the cecal
ligation and puncture (CLP) procedure [21]. In these mice,
melatonin administration increased the survival rate by 28%
as compared with vehicle-treated animals.
In another experimental model for septic shock, that is,
the systemic administration of zymosan A that causes a
massive release of proinflammatory mediators like TNF-α,
IL-6, prostaglandins, NO, and ROS, a 100% mortality was
observed, whereas the simultaneous administration of
zymosan and melatonin (0.8 mg/kg) resulted in only 27%
mortality rate [22].
The CLP model of sepsis was used to further understand
the possible involvement of mitochondrial NOS and
melatonin in the pathophysiology of sepsis by examining
the changes in mitochondrial constitutive and iNOS activity
and mitochondrial function in skeletal muscles of wild-type
(iNOS
+/+
) and iNOS knockout mice (iNOS
−/−
)[23]. When 4
doses of melatonin (30 mg/kg) were injected IP in iNOS
+/+
mice, but not in iNOS
−/−
mice, sepsis increased mitochon-
drial NOS activity. Melatonin administration counteracted
sepsis-induced mitochondrial iNOS activity in iNOS
+/+
mice, but did not affect mitochondrial constitutive NOS
activity in either type of mice [23]. Mitochondrial nitrite
significantly increased in iNOS
+/+
mice after sepsis, whereas
melatonin treatment reduced nitrite levels to control values.
Lipid peroxidation, which was increased in septic iNOS
+/+
mice, decreased significantly after melatonin administration.
Sepsis significantly reduced the mitochondrial content of
total glutathione (GSH) in iNOS
+/+
mice and increased the
oxidized glutathione to GSH ratio, indicating a loss of
reduced GSH. These changes in mitochondrial GSH pool
during sepsis were counteracted by melatonin administration
[23]. As far as the electron transport chain, complex I, II, II,
and IV activities were significantly reduced in septic NOS
+/+
mice by about half; and the administration of melatonin not
only prevented the inhibition of complex activities induced
by sepsis but also increased their activities above their basal
values [23].
Although extensively studied, the pathophysiology of
sepsis-associated multiorgan failure remains undefined
[4,24]. It has been proposed that a key defect in sepsis is
656.e3Melatonin in septic shock: Some recent concepts
the disruption of oxidative phosphorylation within mito-
chondria [25]. The result is an inability of the cell to use
molecular oxygen for adenosine triphosphate production,
despite adequate oxygen availability. Melatonin normalized
the production of adenosine triphosphate in iNOS
+/+
septic
mice, without affecting iNOS
−/−
animals [26].
The efficacy of melatonin to prevent intraperitoneal sepsis
and the associated multiple organ dysfunction syndrome was
evaluated in rats subjected to the CLP procedure [27].
Melatonin was administered 3, 6, and 12 hours after CLP. The
pressor response to norepinephrine was assessed at 0, 3, 9,
and 18 hours after CLP surgery. Animals that received CLP
alone showed a significantly progressive decrease in mean
arterial blood pressure from 9 to 18 hours (ie, from about 120
to 70 mm Hg). In the animals that received CLP plus
melatonin (0.3 mg/kg intravenously at 3 and 9 hours after
CLP), the delayed fall in blood pressure was prevented [27].
The administration of melatonin completely restored the
norepinephrine-induced vasomotor response back to normal.
With regard to biochemical indexes of liver dysfunction, the
rise in plasma glutamate-pyruvate transaminase and gluta-
mate-oxaloacetate transaminase caused by CLP was pre-
vented by melatonin treatment, as was the increase in
creatinine, blood urea nitrogen, and lactate dehydrogenase
(indicators of renal failure and cellular damage) in response to
CLP [27].
Several cytokines released during sepsis, especially IL-1β,
directly act on blood vessels, inducing vasodilatation through
rapid production of platelet-activating factor and NO. In CLP
rats, melatonin treatment diminished plasma NO and IL-1β
concentrations, aortic superoxide levels, and the infiltration
of polymorphonuclear neutrophils in lung and liver [27].
Therefore, Wu et al [27] attributed the beneficial effects of
melatonin in the CLP septic model to inhibition of IL-βand
NO production, O
2
−
formation, and polymorphonuclear
infiltration in organs. In a previous study, it had been
observed that melatonin (10 mg/kg, IP) 30 minutes before
and 6 hours after CLP counteracted the inhibition of in vitro
ileal and bladder contractility caused by sepsis [28].
Considering that micromolar melatonin concentrations
could be locally achieved through production by activated
immune competent cells, extrapineal melatonin could have a
protective effect against tissue injury in multiple organ
dysfunction syndrome [29].
4. Melatonin studies in septic patients
Several studies have measured melatonin levels in
critically ill patients to find out a possible correlation
between melatonin and intensity of septic shock. In one of
those studies carried out in intensive care unit (ICU) patients,
17 septic ICU patients, 7 ICU nonseptic patients, and 21
controls were examined [30]. 6-Sulfatoxymelatonin was
determined in urine samples taken at 4-hour intervals over a
total period of 24 hours. Urinary 6-sulfatoxymelatonin
exhibited significant circadian periodicity in only 1 of 17
septic patients vs 6 of 7 in nonseptic patients and 18 of 23 in
normal controls. The phase amplitude (an index of the
maximal levels attained at peak concentrations) was
significantly lower in septic patients. In sepsis survivors, 6-
sulfatoxymelatonin excretion profiles tended to normalize,
but still lacked a significant circadian rhythm at ICU
discharge [30].
In another study, melatonin levels in blood and urine were
studied over 3 consecutive days in 8 critically ill patients
during deep sedation and mechanical ventilation at the ICU
[31]. The circadian rhythm of melatonin release was
abolished in all but one patient, who recovered much more
quickly than the others [31].
Biochemical markers for the circadian rhythm were
studied in 16 patients treated at the ICU of 2 regional
hospitals in Sweden [32]. All urine excreted between 7:00
AM and 10:00 PM (day) and between 10:00 PM and 7:00 AM
(night) was collected and sampled throughout the entire ICU
period (median, 10 days) for the excretion of 6-sulfatox-
ymelatonin and free cortisol. Overall excretion of 6-
sulfatoxymelatonin was lower and cortisol excretion was
higher than reported for healthy reference populations [32].
Mechanical ventilation was associated with a markedly
lower 6-sulfatoxymelatonin excretion (median, 198 ng/h)
compared with periods without such help (555 ng/h),
whereas infusion of adrenergic drugs increased 6-sulfatox-
ymelatonin excretion significantly. Five patients (31%)
showed a virtually absent melatonin excretion for 24 hours
or more. The diurnal rhythms were consistently or
periodically disturbed in 65% and 75% of the patients [32].
Perras et al [33] measured serum melatonin concentra-
tions at 2:00 AM in the first night in hospital in 302 patients
consecutively admitted to the ICU. Correlations between
illness severity (Acute Physiology and Chronic Health
Evaluation II score and Therapeutic Intervention Scoring
System) and melatonin levels were assessed. Overall
analysis for the whole group of patients revealed no or
very weak correlation between nocturnal serum melatonin
levels and illness severity. In contrast, analysis of subgroups
indicated that, in the 14 patients with severe sepsis, Acute
Physiology and Chronic Health Evaluation and Therapeutic
Intervention Scoring System scores were correlated nega-
tively with nocturnal melatonin concentrations. In contrast,
melatonin levels and illness severity were not correlated in
patients admitted for coronary syndrome, intoxication,
gastrointestinal bleeding, pneumonia, or stroke [33].
The alteration of the sleep-wake cycle, the augmented
oxidative/nitrosative stress, and the altered inflammatory
reaction seen in patients with septic shock render them
suitable for melatonin therapy [34]. To assess in critically ill
patients receiving mechanical ventilation the effect of
exogenous melatonin on nocturnal sleep quantity, a
randomized, double-blind, placebo-controlled trial including
24 patients who had undergone a tracheostomy was
656.e4 V. Srinivasan et al.
performed [35]. Oral melatonin (10 mg) or placebo was
administered at 9:00 PM for 4 nights. Nocturnal sleep was
evaluated using the bispectral index (a signal-processing
electroencephalographic technique). Actigraphy and subjec-
tive assessment of sleep were also used. Nocturnal sleep time
was 2.5 hours in the placebo group, and melatonin use was
associated with a 1-hour increase in nocturnal sleep [35].
Based on the supraphysiologic melatonin levels detected in
plasma at the end of the night, the authors concluded that a
lower amount of melatonin (1-2 mg) would probably be
enough to improve sleep. However, amounts of melatonin in
the 10-mg range or higher should be needed to warrant the
effect on reduction of ischemic reperfusion injury, preven-
tion of multiorgan failure, or treatment of sepsis.
From a different perspective, namely, to curtail oxidative
stress, a number of clinical studies performed by Gitto and
coworkers [36] have shown that melatonin reduces oxidative
stress in newborns with sepsis, distress, or other conditions
where there is excessive ROS production. In the first of these
studies, a product of lipid peroxidation, MDA, and the nitrite/
nitrate levels were measured in the serum of 20 asphyxiated
newborns before and after treatment with melatonin given
within the first 6 hours of life. Ten asphyxiated newborns
received a total of 80 mg of melatonin (8 doses of 10 mg each
separated by 2-hour intervals) orally. One blood sample was
collected before melatonin administration, and 2 additional
blood samples (at 12 and 24 hours) were collected after
giving melatonin. Serum MDA and nitrite/nitrate concentra-
tions in newborns with asphyxia before treatment were
significantly higher than those in infants without asphyxia. In
the asphyxiated newborns given melatonin, there were
significant reductions in MDA and nitrite/nitrate levels.
Three of the 10 asphyxiated children not given melatonin
died within 72 hours after birth; none of the 10 asphyxiated
newborns given melatonin died [36].
In a second study, a total of 20 mg melatonin was
administered orally in 2 doses of 10 mg each with a 1-hour
interval. The changes in the clinical status and the serum
levels of the lipid peroxidation products MDA and 4-HDA
were recorded in 10 septic newborns treated with the
antioxidant melatonin given within the first 12 hours after
diagnosis. Ten other septic newborns in a comparable state
were used as “septic”controls, whereas 10 healthy newborns
served as normal controls. Serum MDA + 4-HDA concen-
trations in newborns with sepsis were significantly higher
than those in healthy infants without sepsis, and they were
significantly reduced by melatonin. Melatonin also improved
the clinical outcome of the septic newborns as judged by
measurement of sepsis-related serum parameters after 24 and
48 hours [36].
Gitto et al also examined whether melatonin treatment
would lower IL-6, IL-8, TNF-α, and nitrite/nitrate levels in
24 newborns with respiratory distress syndrome grade III or
IV diagnosed within the first 6 hours of life. Compared with
the melatonin-treated respiratory distress syndrome
newborns, in the untreated infants, the concentrations of
IL-6, IL-8, and TNF-αwere significantly higher at 24 hours,
72 hours, and 7 days after onset of the study. In addition,
nitrite/nitrate levels at all time points were higher in the
untreated respiratory distress syndrome newborns than in the
melatonin-treated babies. After melatonin administration,
nitrite/nitrate levels decreased significantly, whereas they
remained high and increased further in the respiratory
distress syndrome infants not given melatonin.
Proinflammatory cytokines (IL-6, IL-8, and TNF-α) and
the clinical status were examined in 110 preterm newborns
with respiratory distress syndrome ventilated before and after
treatment with melatonin. When comparing serum levels of
IL-6, IL-8, and TNF-αfor 2 groups, melatonin treatment
clearly had anti-inflammatory effects [36]. In conclusion,
these studies indicate that melatonin lowers IL-IL-6, IL-8,
TNF-α, and nitrite/nitrate levels and modifies serum
inflammatory parameters in surgical neonates, improving
their clinical course.
5. Conclusion
Active research continues to define the principal altera-
tions in sepsis, although significant challenges remain before
this devastating process is understood and conquered.
Melatonin has entered this arena because it has a promise
as an appropriate add-on pharmacologic tool in sepsis.
Although understanding of melatonin's action in the
pathogenesis of septic shock is yet to be achieved, studies
so far point out that melatonin, through its immunomodu-
latory, antioxidant, and antiapoptotic actions, may exert
beneficial effects in septic shock and multiorgan failure.
However, larger randomized controlled clinical trials are
necessary to confirm the potential benefits of melatonin
therapy before it can be routinely used in the postoperative or
critically ill patients [37].
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.jcrc.2010.03.006.
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