Wikipedia

Adrenaline

(Redirected fromEpinephrine)
This article is about the natural hormone. For this substance when used as a drug, seeEpinephrine (medication).For other uses, seeAdrenaline (disambiguation).

Adrenaline,also known asepinephrine,is ahormoneandmedication[10][11]which is involved in regulating visceral functions (e.g., respiration).[10][12]It appears as a white microcrystalline granule.[13]Adrenaline is normally produced by theadrenal glandsand by a small number ofneuronsin themedulla oblongata.[14]It plays an essential role in thefight-or-flight responseby increasing blood flow to muscles,heart outputby acting on theSA node,[15]pupil dilation response,andblood sugar level.[16][17]It does this by binding toAlphaandbeta receptors.[17]It is found in many animals, including humans, and somesingle-celled organisms.[18][19]It has also been isolated from the plantScoparia dulcisfound in Northern Vietnam.[20]

Epinephrine
Skeletal formula of adrenaline
Skeletal formulaof adrenaline
Ball-and-stick model of epinephrine (adrenaline) molecule
Ball-and-stick modelof thezwitterionicform of adrenaline found in thecrystal structure[1]
Clinical data
Trade namesEpipen, Adrenaclick, others
Other namesEpinephrine, adrenaline, adrenalin; 3,4,β-Trihydroxy-N-methylphenethylamine
AHFS/DrugsMonograph
MedlinePlusa603002
License data
Pregnancy
category
  • AU:A
Addiction
liability		None
Routes of
administration		Intravenous,intramuscular,endotracheal,intracardiac,nasal,eye drop
Drug classAdrenergic receptor agonist;Sympathomimetic
ATC code
Physiologicaldata
ReceptorsAdrenergic receptors
MetabolismAdrenergic synapse(MAOandCOMT)
Legal status
Legal status
Pharmacokineticdata
Protein binding15–20%[5][6]
MetabolismAdrenergic synapse(MAOandCOMT)
MetabolitesMetanephrine[7]
Onset of actionRapid[8]
Eliminationhalf-life2 minutes
Duration of actionFew minutes[9]
ExcretionUrine
Identifiers
  • (R)-4-(1-Hydroxy-2-(methylamino)ethyl)benzene-1,2-diol
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard(EPA)
ECHA InfoCard100.000.090Edit this at Wikidata
Chemical and physical data
FormulaC9H13NO3
Molar mass183.207g·mol−1
3D model (JSmol)
Density1.283±0.06 g/cm3@ 20 °C, 760 Torr
  • CNC[C@H](O)c1ccc(O)c(O)c1
  • InChI=1S/C9H13NO3/c1-10-5-9(13)6-2-3-7(11)8(12)4-6/h2-4,9-13H,5H2,1H3/t9-/m0/s1checkY
  • Key:UCTWMZQNUQWSLP-VIFPVBQESA-NcheckY

Medical uses

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Main article:Epinephrine (medication)

As a medication, it is used to treat several conditions, includingallergic reactionanaphylaxis,cardiac arrest,and superficial bleeding.[8]Inhaledadrenaline may be used to improve the symptoms ofcroup.[21]It may also be used forasthmawhen other treatments are not effective. It is givenintravenously,byinjection into a muscle,by inhalation, or byinjection just under the skin.[8]Common side effects include shakiness,anxiety,and sweating. A fast heart rate and high blood pressure may occur. Occasionally it may result in anabnormal heart rhythm.While the safety of its use duringpregnancyandbreastfeedingis unclear, the benefits to the mother must be taken into account.[8]

A case has been made for the use of adrenaline infusion in place of the widely accepted treatment ofinotropesfor preterm infants with clinical cardiovascular compromise. Although sufficient data strongly recommends adrenaline infusions as a viable treatment, more trials are needed to conclusively determine that these infusions will successfully reducemorbidityandmortalityrates among preterm, cardiovascularly compromised infants.[22]

Epinephrine can also be used to treat open-angle glaucoma, as it has been found to increase the outflow of aqueous humor in the eye. This lowers the intraocular pressure in the eye and thus aids in treatment.[23]

Physiological effects

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Theadrenal medullais a major contributor to total circulatingcatecholamines(L-DOPAis at a higher concentration in theplasma),[24]though it contributes over 90% of circulating adrenaline. Little adrenaline is found in other tissues, mostly in scatteredchromaffin cellsand in a small number ofneuronsthat use adrenaline as aneurotransmitter.[25]Followingadrenalectomy,adrenaline disappears below the detection limit in the bloodstream.[26]

Pharmacological doses of adrenaline stimulateα1,α2,β1,β2,andβ3adrenoceptors of thesympathetic nervous system.Sympathetic nerve receptors are classified as adrenergic, based on their responsiveness to adrenaline.[27]The term "adrenergic" is often misinterpreted in that the main sympathetic neurotransmitter isnoradrenaline,rather than adrenaline, as discovered byUlf von Eulerin 1946.[28][29]Adrenaline has a β2adrenoceptor-mediated effect onmetabolismand theairway,with no direct neural connection from thesympathetic gangliato theairway.[30][31][32]

Walter Bradford Cannonoriginally proposed the concept of the adrenal medulla and thesympathetic nervous systembeing involved in the flight, fight, and fright response.[33]But the adrenal medulla, in contrast to the adrenal cortex, is not required for survival. In adrenalectomized patients, hemodynamic and metabolic responses to stimuli such as hypoglycemia and exercise remain normal.[34][35]

Exercise

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One physiological stimulus to adrenaline secretion is exercise. This was first demonstrated by measuring the dilation of a (denervated) pupil of a cat on a treadmill,[36]later confirmed using a biological assay of urine samples.[37]Biochemical methods for measuring catecholamines in plasma were published from 1950 onwards.[38]Although much valuable work has been published using fluorimetric assays to measure total catecholamine concentrations, the method is too non-specific and insensitive to accurately determine the very small quantities of adrenaline in plasma. The development of extraction methods and enzyme–isotope derivate radio-enzymatic assays (REA) transformed the analysis down to a sensitivity of 1 pg for adrenaline.[39]Early REA plasma assays indicated that adrenaline and total catecholamines rise late in exercise, mostly when anaerobic metabolism commences.[40][41][42]

During exercise, the adrenaline blood concentration rises partially from the increased secretion of the adrenal medulla and partly from the decreased metabolism of adrenaline due to reduced blood flow to the liver.[43]Infusion of adrenaline to reproduce exercise circulating concentrations of adrenaline in subjects at rest has little hemodynamic effect other than a slight β2-mediated fall in diastolic blood pressure.[44][45]Infusion of adrenaline well within the physiological range suppresses human airway hyper-reactivity sufficiently to antagonize the constrictor effects of inhaled histamine.[46]

A link between the sympathetic nervous system and the lungs was shown in 1887 when Grossman showed that stimulation of cardiac accelerator nerves reversed muscarine-induced airway constriction.[47]In experiments in the dog, where the sympathetic chain was cut at the level of the diaphragm, Jackson showed that there was no direct sympathetic innervation to the lung, but bronchoconstriction was reversed by the release of adrenaline from the adrenal medulla.[48]An increased incidence of asthma has not been reported for adrenalectomized patients; those with a predisposition to asthma will have some protection from airway hyper-reactivity from their corticosteroid replacement therapy. Exercise induces progressive airway dilation in normal subjects that correlates with workload and is not prevented by beta-blockade.[49]The progressive airway dilation with increasing exercise is mediated by a progressive reduction in resting vagal tone. Beta blockade with propranolol causes a rebound in airway resistance after exercise in normal subjects over the same time course as the bronchoconstriction seen with exercise-induced asthma.[50]The reduction in airway resistance during exercise reduces the work of breathing.[51]

Emotional responses

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Every emotional response has a behavioral, an autonomic, and a hormonal component. The hormonal component includes the release of adrenaline, an adrenomedullary response to stress controlled by thesympathetic nervous system.The major emotion studied in relation to adrenaline is fear. In an experiment, subjects who were injected with adrenaline expressed more negative and fewer positive facial expressions to fear films compared to a control group. These subjects also reported a more intense fear from the films and greater mean intensity of negative memories than control subjects.[52]The findings from this study demonstrate that there are learned associations between negative feelings and levels of adrenaline. Overall, the greater amount of adrenaline is positively correlated with an aroused state ofnegative emotions.These findings can be an effect in part that adrenaline elicits physiological sympathetic responses, including an increased heart rate and knee shaking, which can be attributed to the feeling of fear regardless of the actual level of fear elicited from the video. Although studies have found a definite relation between adrenaline and fear, other emotions have not had such results. In the same study, subjects did not express a greater amusement to an amusement film nor greater anger to an anger film.[52]Similar findings were also supported in a study that involved rodent subjects that either were able or unable to produce adrenaline. Findings support the idea that adrenaline has a role in facilitating the encoding of emotionally arousing events, contributing to higher levels of arousal due to fear.[53]

Memory

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It has been found that adrenergic hormones, such as adrenaline, can produce retrograde enhancement oflong-term memoryin humans. The release of adrenaline due to emotionally stressful events, which is endogenous adrenaline, can modulate memory consolidation of the events, ensuring memory strength that is proportional to memory importance. Post-learning adrenaline activity also interacts with the degree of arousal associated with the initial coding.[54]There is evidence that suggests adrenaline does have a role in long-term stress adaptation and emotional memory encoding specifically. Adrenaline may also play a role in elevating arousal and fear memory under particular pathological conditions, includingpost-traumatic stress disorder.[53]Overall, "Extensive evidence indicates that epinephrine (EPI) modulates memory consolidation for emotionally arousing tasks in animals and human subjects."[55]Studies have also found that recognition memory involving adrenaline depends on a mechanism that depends on β adrenoceptors.[55]Adrenaline does not readily cross the blood-brain barrier, so its effects on memory consolidation are at least partly initiated by β adrenoceptors in the periphery. Studies have found thatsotalol,aβ adrenoceptor antagonistthat also does not readily enter the brain, blocks the enhancing effects of peripherally administered adrenaline on memory.[56]These findings suggest that β adrenoceptors are necessary for adrenaline to have an impact on memory consolidation.[57][58]

Pathology

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Increased adrenaline secretion is observed inpheochromocytoma,hypoglycemia,myocardial infarction,and to a lesser degree, inessential tremor(also known as benign, familial, or idiopathic tremor). A general increase in sympathetic neural activity is usually accompanied by increased adrenaline secretion, but there is selectivity during hypoxia and hypoglycemia, when the ratio of adrenaline to noradrenaline is considerably increased.[59][60][61]Therefore, there must be some autonomy of the adrenal medulla from the rest of the sympathetic system.

Myocardial infarction is associated with high levels of circulating adrenaline and noradrenaline, particularly in cardiogenic shock.[62][63]

Benign familial tremor (essential tremor) (BFT) is responsive to peripheral β adrenergic blockers, and β2-stimulation is known to cause tremor. Patients with BFT were found to have increased plasma adrenaline but not noradrenaline.[64][65]

Low or absent concentrations of adrenaline can be seen in autonomic neuropathy or following adrenalectomy. Failure of the adrenal cortex, as withAddison's disease,can suppress adrenaline secretion as the activity of the synthesizing enzyme,phenylethanolamine-N-methyltransferase,depends on the high concentration of cortisol that drains from the cortex to the medulla.[66][67][68]

Terminology

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In 1901,Jōkichi Takaminepatented a purified extract from theadrenal glands,which wastrademarkedbyParke, Davis & Coin the US.[69]TheBritish Approved NameandEuropean Pharmacopoeiaterm for this drug is henceadrenaline(fromLatinad,"on", andrēnālis,"of the kidney", fromren,"kidney" ).[70]

However, the pharmacologistJohn Abelhad already prepared an extract from adrenal glands as early as 1897, and he coined the nameepinephrineto describe it (fromAncient Greekἐπῐ́(epí), "upon", andνεφρός(nephrós), "kidney" ).[69]As the termAdrenalinewas a registered trademark in the US,[69]and in the belief that Abel's extract was the same as Takamine's (a belief since disputed), epinephrine instead became[when?]the generic name used in the US[69]and remains thepharmaceutical'sUnited States Adopted NameandInternational Nonproprietary Name(though the name adrenaline is frequently used[71]).

The terminology is now one of the few differences between the INN and BAN systems of names.[72]Although European health professionals and scientists preferentially use the termadrenaline,the converse is true among American health professionals and scientists. Nevertheless, even among the latter, receptors for this substance are calledadrenergic receptorsoradrenoceptors,and pharmaceuticals that mimic its effects are often calledadrenergics.The history of adrenaline and epinephrine is reviewed by Rao.[73]

Mechanism of action

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See also:Adrenergic receptor
Physiologic responses to adrenaline by organ
Organ Effects
Heart Increases heart rate; contractility; conduction across AV node
Lungs Increases respiratory rate; bronchodilation
Liver Stimulatesglycogenolysis
Muscle Stimulates glycogenolysis andglycolysis
Brain Increased cerebral tissue oxygenation
Systemic Vasoconstrictionandvasodilation
Triggerslipolysis
Muscle contraction
7x speed timelapse video of fish melanophores responding to 200μMadrenaline

As a hormone, adrenaline acts on nearly all body tissues by binding toadrenergic receptors.Its effects on various tissues depend on the type of tissue and expression of specific forms ofadrenergic receptors.For example, high levels of adrenaline causesmooth musclerelaxation in the airways but causes contraction of the smooth muscle that lines mostarterioles.

Adrenaline is a nonselectiveagonistof all adrenergic receptors, including the major subtypesα1,α2,β1,β2,andβ3.[74]Adrenaline's binding to these receptors triggers a number of metabolic changes. Binding to α-adrenergic receptors inhibitsinsulinsecretion by thepancreas,stimulatesglycogenolysisin theliverandmuscle,[75]and stimulatesglycolysisand inhibits insulin-mediatedglycogenesisin muscle.[76][77]β adrenergic receptor binding triggersglucagonsecretion in the pancreas, increasedadrenocorticotropic hormone(ACTH) secretion by thepituitary gland,and increasedlipolysisbyadipose tissue.Together, these effects increaseblood glucoseandfatty acids,providing substrates for energy production within cells throughout the body.[77]Binding of β adrenergic receptor also increases the production of cyclic AMP.[78]

Adrenaline causesliver cellsto releaseglucoseinto the blood, acting through both Alpha and beta-adrenergic receptors to stimulate glycogenolysis. Adrenaline binds to β2receptors on liver cells, which changes conformation and helps Gs,aheterotrimeric G protein,exchange GDP to GTP. This trimeric G protein dissociates toGsAlphaand Gsbeta/gamma subunits. GsAlpha stimulatesadenylyl cyclase,thus convertingadenosine triphosphateintocyclic adenosine monophosphate(AMP). Cyclic AMP activatesprotein kinase A.Protein kinase A phosphorylates and partially activatesphosphorylase kinase.Adrenaline also binds to α1adrenergic receptors, causing an increase ininositol trisphosphate,inducing calcium ions to enter the cytoplasm. Calcium ions bind tocalmodulin,which leads to further activation of phosphorylase kinase. Phosphorylase kinase phosphorylatesglycogen phosphorylase,which then breaks downglycogenleading to the production of glucose.[79]

Adrenaline also has significant effects on the cardiovascular system. It increases peripheral resistance viaα1receptor-dependentvasoconstrictionand increasescardiac outputby binding to β1receptors. The goal of reducing peripheral circulation is to increase coronary and cerebral perfusion pressures and therefore increase oxygen exchange at the cellular level.[80][81]While adrenaline does increase aortic, cerebral, and carotid circulation pressure, it lowers carotid blood flow andend-tidal CO2or ETCO2levels. It appears that adrenaline improves microcirculation at the expense of the capillary beds where perfusion takes place.[82]

Measurement in biological fluids

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Adrenaline may be quantified in blood, plasma, or serum as a diagnostic aid, to monitor therapeutic administration, or to identify the causative agent in a potential poisoning victim. Endogenous plasma adrenaline concentrations in resting adults usually are less than 10 ng/L, but they may increase by 10-fold during exercise and by 50-fold or more during times of stress.Pheochromocytomapatients often have plasma adrenaline levels of 1000–10,000 ng/L. Parenteral administration of adrenaline to acute-care cardiac patients can produce plasma concentrations of 10,000 to 100,000 ng/L.[83][84]

Biosynthesis

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The biosynthesis of adrenaline involves a series of enzymatic reactions.

In chemical terms, adrenaline is one of a group ofmonoaminescalled thecatecholamines.Adrenaline is synthesized in thechromaffin cellsof theadrenal gland'sadrenal medullaand a small number of neurons in themedulla oblongatain the brain through ametabolic pathwaythat converts theamino acidsphenylalanineandtyrosineinto a series of metabolic intermediates and, ultimately, adrenaline.[10][12][85]Tyrosine is first oxidized toL-DOPAbytyrosine hydroxylase;this is the rate-limiting step. Then it is subsequently decarboxylated to givedopamineby DOPA decarboxylase (aromaticL-amino acid decarboxylase). Dopamine is then converted tonoradrenalinebydopamine beta-hydroxylase,which utilizes ascorbic acid (vitamin C) and copper. The final step in adrenaline biosynthesis is themethylationof theprimary amineof noradrenaline. This reaction is catalyzed by the enzymephenylethanolamineN-methyltransferase(PNMT), which utilizesS-adenosyl methionine(SAMe) as themethyldonor.[86]While PNMT is found primarily in thecytosolof theendocrinecells of theadrenal medulla(also known aschromaffin cells), it has been detected at low levels in both theheartandbrain.[87]

Biosynthetic pathways forcatecholaminesandtrace aminesin thehuman brain[88][89][90]
Epinephrine is produced in a small group of neurons in the human brain (specifically, in themedulla oblongata) via the metabolic pathway shown above.[12]

Regulation

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The major physiologic triggers of adrenaline release center uponstresses,such as physical threat, excitement, noise, bright lights, and high or low ambient temperature. All of these stimuli are processed in thecentral nervous system.[91]

Adrenocorticotropic hormone(ACTH) and thesympathetic nervous systemstimulate the synthesis of adrenaline precursors by enhancing the activity oftyrosine hydroxylaseanddopamine β-hydroxylase,two key enzymes involved in catecholamine synthesis.[citation needed]ACTH also stimulates theadrenal cortexto releasecortisol,which increases the expression of PNMT in chromaffin cells, enhancing adrenaline synthesis. This is most often done in response to stress.[citation needed]The sympathetic nervous system, acting viasplanchnic nervesto the adrenal medulla, stimulates the release of adrenaline.Acetylcholinereleased by preganglionic sympathetic fibers of these nerves acts onnicotinic acetylcholine receptors,causing cell depolarization and an influx ofcalciumthroughvoltage-gated calcium channels.Calcium triggers theexocytosisof chromaffin granules and, thus, the release of adrenaline (and noradrenaline) into the bloodstream.[citation needed]For noradrenaline to be acted upon by PNMT in the cytosol, it must first be shipped out ofgranulesof the chromaffin cells. This may occur via the catecholamine-H+exchangerVMAT1.VMAT1 is also responsible for transporting newly synthesized adrenaline from the cytosol back into chromaffin granules in preparation for release.[92]

Unlike many other hormones, adrenaline (as with other catecholamines) does not exertnegative feedbacktodown-regulateits own synthesis. Abnormal adrenaline levels can occur in various conditions, such as surreptitious adrenaline administration,pheochromocytoma,and other tumors of thesympathetic ganglia.

Its action is terminated with reuptake into nerve terminal endings, some minute dilution, and metabolism bymonoamine oxidase[93]andcatechol-O-methyl transferaseinto3,4-Dihydroxymandelic acidandMetanephrine.

History

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Main article:History of catecholamine research

Extracts of theadrenal glandwere first obtained by Polish physiologistNapoleon Cybulskiin 1895.[94]These extracts, which he callednadnerczyna( "adrenalin" ), contained adrenaline and other catecholamines.[95]American ophthalmologistWilliam H. Batesdiscovered adrenaline's usage for eye surgeries prior to 20 April 1896.[96]In 1897,John Jacob Abel(1857–1938), the father of modern pharmacology, found a natural substance produced by the adrenal glands that he named epinephrine. The first hormone to be identified, it remains a crucial, first-line treatment for cardiac arrests, severe allergic reactions, and other conditions. In 1901, Jokichi Takamine successfully isolated and purified the hormone from the adrenal glands of sheep and oxen.[97]Adrenaline was first synthesized in the laboratory byFriedrich StolzandHenry Drysdale Dakin,independently, in 1904.[98]

Although secretin is mentioned as the first hormone, adrenaline is the first hormone since the discovery of the activity of adrenal extract on blood pressure was observed in 1895 before that ofsecretinin 1902.[73]In 1895, George Oliver (1841–1915), a general practitioner in North Yorkshire, and Edward Albert Schäfer (1850–1935), a physiologist at University College of London published a paper about the active component ofadrenal glandextract causing the increase in blood pressure and heart rate was from the medulla, but not the cortex of the adrenal gland.[99]In 1897,John Jacob Abel(1857–1938) ofJohns Hopkins University,the first chairman of the first US department of pharmacology, found a compound called epinephrine with the molecular formula of C17H15NO4.[73]Abel claimed his principle from adrenal gland extract was active.

In 1900, Jōkichi Takamine (1854–1922), a Japanese chemist, worked with his assistant,Keizo Uenaka[ja](1876–1960), to purify a 2000 times more active principle than epinephrine from the adrenal gland, named adrenaline with the molecular formula C10H15NO3.[73][99]Additionally, in 1900 Thomas Aldrich of Parke-Davis Scientific Laboratory also purified adrenaline independently. Takamine and Parke-Davis later in 1901 both got the patent for adrenaline. The fight for terminology between adrenaline and epinephrine was not ended until the first adrenaline structural discovery by Hermann Pauly (1870–1950) in 1903 and the first adrenaline synthesis byFriedrich Stolz(1860–1936), a German chemist in 1904. They both believed that Takamine's compound was the active principle while Abel's compound was the inactive one.[citation needed]Stolz synthesized adrenaline from its ketone form (adrenalone).[100]

Society and culture

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Adrenaline junkie

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See also:Novelty seeking

Anadrenaline junkieis someone who engages in sensation-seeking behavior through "the pursuit of novel and intense experiences without regard for physical, social, legal or financial risk".[101]Such activities include extreme and risky sports, substance abuse, unsafe sex, and crime. The term relates to the increase in circulating levels of adrenaline during physiologicalstress.[102]Such an increase in the circulating concentration of adrenaline is secondary to the activation of the sympathetic nerves innervating the adrenal medulla, as it is rapid and not present in animals where the adrenal gland has been removed.[103]Although such stress triggers adrenaline release, it also activates many other responses within the central nervous systemreward system,which drives behavioral responses; while the circulating adrenaline concentration is present, it may not drive behavior. Nevertheless, adrenaline infusion alone does increase alertness[104]and has roles in the brain, including the augmentation of memory consolidation.[102]

Strength

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Main article:Hysterical strength

Adrenaline has been implicated in feats of great strength, often occurring in times of crisis. For example, there are stories of a parent lifting part of a car when their child is trapped underneath, showcasing the insane amount of potential the body can endure under stress and highlighting the profound effects of adrenaline in unlocking extraordinary physical abilities.[105][106]

See also

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References

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