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Mandelic acid (Phenylglycollic acid) C6H6CH(OH)COOH may
be obtained by boiling amygdalin with HCl. It may also be
prepared from benzaldehyde by treatment with HCN and hydro-
lysing the resulting hydroxy cyanide:

CeHBCHO + HCN = C6H6CH(OH)CN
C6H6CH(OH)CN + 2H2O = C6HbCH(0H)C00H + NH,

Salidn C13H18O7 is the glucoside of Willow bark. On hydroly-
sis, it yields glucose and saligenin.

yOB (1)
C13H18O7 + H2O = C6H4V + CeHiaOe

^CHaOH (2)
Saligenin

Saligenin is the alcohol corresponding to salicylic acid and on
oxidation will yield salicylic aldehyde and salicylic acid.

13



Digitized by CjOOQ IC



194



CHEMICAL PHARMACOLOGY



1. Styrolene Derivatives. — This group contains phenylen-
ethylene or styrolene CeHgCHiCH. Strophanthin and phlorid-
zin are the most important representatives.

Phloridzin C21H24O10.2H2O, is a glucoside prepared from the
root bark of the apple, pear, plum, cherry, and various other
members of the rosacese. It is much used in experimental work
and its most pronounced action is the prodiuction of glycosuria,
with a simultaneous hypoglycsemia. It is decomposed by dilute
acids into a glucose and phloretin:

C21H24O102H2O — > Ci6Hi406 + C5H12O6

Phloretin Glucose



PAtore^m has the following formula:
OH



OH



CO-CH-

I

OH CH3



OH



On decomposition, phloretin yields phloroglucin and phloretinic
acid:



OH



CibHuOs + H2O



OH



+ C6H



OH



\



Phloroglucin



OH (1)
CH(CH8)COOH(4)

Phloretinic acid '



Strophanthin. — Several substances have been described under
this term. Strophanthinum or amorphous strophanthin is
prepared from strophanthus hispidus and Kombe. Ouabain



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ANTHRACENES



195



from strophanthus gratus, known also as g. strophanthin-crystal-
line, is considered a purer product than the amorphous forms.
The formula C30H46O129H2O has been assigned to it.

Amand, Kohn, and Kulisch isolated a substance from stro-
phanthus Komb6, which gave the formula C8;H480i2 which on
hydrolysis yielded strophanthidin C19H28O4 and a mixtiu-e of
sugars.

4. Anthracene or Anthraquinoiie Derivatives. — Many of the
anthracene purgatives principles belong in this group. Emodin
and chrysophanic acid occur as glucosides or rhamnosides.
Digitoxin, saponin, and strophanthin may be placed here also,
as in the previous group but the chemistry of these bodies is so
indefinite that a final classification cannot be made.

Chrysophanic acid or dioxy methylianthra-quinon




and Emodin or trioxy methyl

anthraquinone
O
CHs II OH




occur in rhubarb, frangula, senna, aloes, etc. The purgative
property of these bodies has been attributed to the anthracene
group, to the ketone or quinone groups, and to various side
chains. Various synthetic bodies of this class have been prepared



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196 CHEMICAL PHABMACOLOGT

commencing with aloin. These are not so efficient as purgatives,
as the natural products, because they are too rapidly hydrolysed
and absorbed from the intestine. Drugs used for their direct action
in the intestine should not be rapidly absorbed. It is by reason
of delayed absorption that opium is more efficient in depressing
movements of the intestine than morphine.

SAPONIN OR SAPONINS

The term saponin was originally restricted to the specific
substance obtained from the root of saponaria rubra and S. alba.
The term now includes a series of glucosides of which the empir-
ical formula alone is known. They correspond to the general
formula C8H2N8O10, and are found in many plants as saponaria
officinalis, senega, quillaja, digitalis, sarsaparilla, etc. That
isolated from saponaria officinalis has the formula CigHsoOio.
On hydrolysis, it yields sapogenin, C14H22O2. Solutions of
saponins foam and become soap-like on shaking. When injected
intravenously, they cause laking of the blood. Some are very
toxic and are classified as sapotoxins. Fish are very sensitive
to saponins. One part of saponin in 100,000 of water will kill
fish, but this does not render them unfit for food, since saponin
in this concentration has no action in the gastro-intestinal tract.

THE DIGITALIS GLUCOSIDES

The chemistry of these is not definitely known, and in addition
to the indefiniteness of the chemistry, the nomenclature is con-
fusing. The principles isolated are probably only approximately
pure. Schmiedeberg and Kiliani have done the principal work on
this subject, but the field has just been touched.

Digitoxin is the most important glucoside. According to
Kiliani, it has the empiric formula C34H64O11. On hydrolysis,
digotoxin yields digitoxose and digitoxigenin. Digitoxose.

C34H640n + H2O = 2C6H12O4 + C22H82O4

Digitoxose Digitoxigenin

crystallizes in crystals and plates, M.P. 102°C. and is of dextro-
rotatory constitution.



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GLUCOSIDES 197

Digitalin, CasHseOu or CasHseOii, according to Kiliani hy-
drolysis into digitalose, digitaligenin, and dextrose:

CagHseOii = C6H12O6 + C7H14O6 + C22H80O8

dextrose digitalose digitaligenin

Digitonin, C65H94O28 or C64H92O28. This is a saponin, soluble
in alcohol from which it crystallizes in fine needles m.p. 235°C.
Onhydrolyses:

C55H94O282H2O = CaiHsoOe + 2CeHi206 + 2C6H12O6
digitonin digitogenin dextrose galactose

The commercial digitalins are impure and variable mixtures of
digitalis principles.

Convallamarin) C23H44O12, and convallarin, C34H62O11, are
two glucosides occurring in convallaria majalis (lily-of-the-valley) .
Convallamarin is soluble in water and alcohol, insoluble in ether
and chloroform, is an acrid glucoside, soluble in water, sparingly
soluble in alcohol, and insoluble in ether and is a saponin-like
glucoside. Little is known of the split products of these glu-
cosides.

DigitaleiUi C22H88O9, was supposed by Schmiedeberg to be a
pure product but is not now considered a chemical entity. The
same is true of digitophyllin.

Glycyrrhizin, C44H68NO18, is the sweet principle of licorice
root. It occurs as the ammonium salt of glycyrrhizic acid,
C44H62(NH)4NOi8, and on hydrolysis it yields glycyrrhetin,
C32H47NO4, and para saccharic acid, CeHioOs.

This acid reduces FehUng's solution and for this reason gly-
cyrrhizin was formerly thought to be a glucoside.

Scillin, from squill, is a mixture of glucosides, the chemistry
of which is unknown.

Helleborin, C36H42O6, is found in black hellebore. On hydroly-
sis it gives helleboresin, C80H38O4, and sugar. Helleborein,
C26H44O16, is another glucoside obtained from the same source.
On hydrolysis it yields helleboretin, C14H20O3, and sugar.



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198 CHEMICAL PHARMACOLOGY

CYANOGENETIC GLUCOSmES

The cyanogenetic glucosides yield hydrocyanic acid on hydroly-
sis. They are of interest chiefly because they are considered
as the connecting link between the carbohydrates and the alka-
loids and other nitrogen containing compounds. Their composi-
tion differs in different plants. Hydrocyanic acid occurs in
many plants sometimes in the free state but mostly in combina-
tion. The nature of many of the compounds is unknown. Many
are in the form of glucosides and it seems that this is the general
condition of hydrocyanic acid in the plant. However,
nitrogen may occur in glucosides in other forms. The cyano-
genetic glucosides occurs chiefly in the buds, seeds, leaves, and
bark.

With regard to the formation of hydrocyanic in the plant
nothing is definitely known. Gautier supposes that it may be
due to the reduction of nitrates by formaldehyde.

The chief cyanogenetic glucosides are:

Amygdalin Dhurrin

Amygdonitrile (Prunasin)

Sambunigrin Gynocardin and

Prulaurasin Vicianin
Phaseolunatin
Lotusin



SOLANIN

Solanin is an alkaloidal glucoside found in all parts of the
potato plant. Its composition is not definitely known. In its
action it resembles the saponins and is a general protoplasm
poison killing bacteria and hemolyzing red cells in extreme
dilutions. Its salts are amorphous and gununy. It is not
affected by alkalies but acids decompose it into solanidin and
a mixture of sugars including. dextrose, rhamnose and galactose.
It dissolves in nitric acid with a yellow color, slowly changing to
red. It gives a green tint with sulphuric acid in alcohol and a
red color with a mixture of sulphuric acid and sodium sulphate.



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INDICAN



199



CONIFERIN

C16H22O8. This glucoside occurs in various coniferous trees
and in asparagus. On hydrolysis with mineral acids or emulsin
it yields glucose and coniferyl alcohol.

C16H22O8 '\~ H2O — > C6H12O6 ~t~ C10H12O8

Coniferyl alcohol.

When coniferyl alcohol is oxidized with potassium bichromate
and sulphuric acid it yields vaniUin. Artificial vanillin was
formerly prepared by this method. It is now prepared by the
oxidation of isoeugenol, which in turn is prepared by boiling
eugenol, the chief constituent of oil of cloves. The relationship
is shown by the formulas:

CH = CHCH2OH CHO CH =CHCH3



OCH3
OH
Coniferyl alcohol.



OCH3 \y OCH3
OH OH

Vanillin Iso-eugenol

CH2.CH;CH2



OCHs
OH
Eugenol
INDICAN

This glucoside occurs in a number of plants, especially indigo
fera anil, I. sumatrana, and I. arrecta. It is decomposed on
hydrolysis into indoxyl and glucose as follows:
CTHcNCO-CeHiiOg -> H2O



C6H4'



\



NH



C(OH)'



?CH -\- C6H12O6



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200



CHEMICAL PHARMACOLOGY



Indoxyl
The dye indigo, is formed from indoxyl by oxidation as follows:



C— H O H O— C



+



NH



C H O HIC



NH



2 Indoxyl
CO GO



NH



NH



Indigo blue



COH HOC



NH



NH



Indigo white

The name indican is also applied to a compound of the
formula:

^ O-OSOsK



\



CH



NH



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ANIMAL GLUCOSIDES 201

which occurs in the urine in cases of intestinal putrefaction, and
is derived from tryptophane, in a manner not yet imderstood.
The relationship is shown by the formula:



HC C C— CHj— CHNHj— COOH

I II II

HC C CH

\h/\nh^

Tryptophane

HC C CH HC C COH

I II II - I II II

HC C CH HC C CH

^CH^^NH^ ^CH^^NH^ •

Indole Indoxyl

HC C CO OC— C CH

I II I I II I

HC C C C C CH

^CH^^NH^ ^NH^^CH^

Indigo blue

The indigo blue in this case is the same as derived from glu-
coside indican. It is now produced synthetically.



ANIMAL GLUCOSIDES

Glucoside like combinations are found in the animal organism.
The importance of these is not well understood. The term glu-
coside itself it must be remembered is not strictly defined. Thier-
felder isolated a glucoside like substance from the human brain



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202 CHEMICAL PHARMACOLOGY

which he called cerebron, a galactoside. On hydrolysis this
3rielded cerebronic acid, sphingosine and galactose:

C48H98NO9 2HjO-tCwH6o08 +
Cerebron Cerebronic acid.

CnHssNO, + CsHi,0«
Sphingosin Galactose.

Cerebron appears to be a mixture of two glucosidic bodies
which have been named Phrenosin (Phren. brain) and kerasin.
Phrenosin yields, sphingosin and galactose kerasin resembles
phrenosin, the differences being mainly that kerasin contains
lignoceric acid C24H48O2 instead of cerebronic. The chemistry
of all these bodies is far from complete. Some of the nucleic
acids contain pentosides, and perhaps other glucosides occiu* in
the brain substance. The importance of these in the animal
economy for the present cannot be evaluated. That they are
*very important can be readily seen when we consider the im-
portance of the nucleins to the life of the cell, and the importance
of the brain tissue in anesthesia, and other drug action, and to
life generally.

THE FUNCTIONS, ACTION, AND FATE OF GLUCOSIDES

The physiological importance of glucosides is not definitely
known. They appear again and again in plants under similar
conditions and it would seem that like the carbohydrates, they are
associated with the metabolism of the plant. As a rule they are
found in greatest amount where metabolism is most active as in
leaves and shoots. Since the time of the maximiun amoimt of
glucosides in plants varies in different plants^ their function in
the different plants may also vary. They may be of value as
food stuffs or as reserve food stuffs. Glucosides as a rule are
hydrolysed readily in the upper part of the alimentary tract.
In the case of the digitalis glucosides none reach the large bowel
imchanged. After large doses some of the glucoside has been
found in the liver but not in other organs. The principles have
been found in the urine and faeces,, so that both kidney and gut



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TESTS FOR GLUCOSIDES 203

take part in the excretion. The hydrolysed products are active
ingredients, though the sugar moiety increases the action. Just
how much of the active part is oxidized in the body is unknown.
The galactoside of the brain is interesting in view of the fact
that all lecithins of vegetable origin are in glucosidic combination.
Galactose, glucose, and pectose, have been identified in these
lecithin glucosides of plants.

Tests for Glucosides

1. Test a 1 per cent, solution of salicin or amygdalin with
Fehhng's solution.

2. Acidify another portion of the glucoside with H2S04,*boil
for 5 minutes, make neutral or sHghtly alkaline with NaOH or
KOH, and apply Fehling's.

3. To another portion add some saliva and keep at body tem-
perature for 15 minutes, then test for sugar.

4. Pulverize some bitter almonds in a. mortar. Note the odor
of the dry powder. Divide into two parts. Mix onfe part with
water at 40®C., and set aside for 15 minutes. Boil the other por-
tion for 5 minutes by adding the boiling water directly to it, and
continuing the boiling. Test both' solutions for HON as follows:
Filter make alkaKne with a few drops of KOH, and add a few
drops of freshly prepared ferrous sulphate solution. After al-
lowing it to stand for 4 minutes acidify with HCl. A Prussian
blue color indicates the presence of HCN. See reaction for N
under alkaloids. Difference between the boiled and the unboiled
portions? Bitter almonds contain a ferment-emulsin.

5. To 5 cc. of the fluid extract of licorice,^' add just enough
1 per cent. Na2C08 to make alkaline. Acidify another 5 cc.
with H2SO4. Compare the taste of the two solutions. Acids are
incompatible with glycyrrhiza.

6. Digitalin: Use only a trace of the dry substance in making
the tests, (a) The soJuCion in H2SO4 is yellow. This turns
blood red or violet on adding a drop of HNOs or PeiCU. (b)
Dissolve a trace of the dry substance jn a test tube. Add a
riiere trace of PejCU with a glass rod. Add an equal voliune
of cone. H2SO4 without mixing. If digitalin is present' |there
is a persistent carmine zone at the point of contact, (c) Place



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204 CHEBHCAL PHARMACOLOGY

a small piece of the dry substance on a white plate. Add a
drop of FeiCU and cone. H2SO4 without mixing. A carmine
or violet zone which changes to indigo results (Kiliani). (d)
Physiologic test. This must be taken into consideration with
the above. The slowing and systolic standstill of the frog's
heart is characteristic.

7. To a portion of a glucosidal solution add 2 cc. of saliva.
Keep it at l0°C. for 15 minutes and test for sugar as in 2.

8. Guignard's test for cyanbgenetic glucosides. Strips of
filter paper are dipped in 1 per cent, picric acid solution and
dried; they are now moistened with 10 per cent, solution of
NaaCOa and again dried. In the fumes of HCN, these papers
turn red due to the formation of potassium isopurpurate. If
these papers be suspended over a solution containing HCN
they become red gradually. The rate depending on the amoimt
of acid present. Hydrogen sulphide gives this same reaction
due to the formation of picraminic acid, and sugar heated in
a solution of alkaUne picric acid also gives the red color.



XXIL BITTER PRINCIPLES

Bitters have nothing in common except their bitter taste, and
cannot be classified chemically. All distinctly bitter extractives
other than alkaloids, glucosides, and neutral principles that are
not toxic, are included under the term bitters. The neutral
principles differ from the bitters only in their higher activity and
toxicity.

Tests to Distinguish Bitters from Other Bodies

1. They are not precipitated by alkaloidal reagents — different
from alkaloids.

2. They do not yield sugar on hydrolysis — different from
glucosides.

3. Bitters are physiologically rather inert — different from
neutral principles and alkaloids.

Pharmacologic Classification. — Bitters may.be conveniently
placed under foxir heads:



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BITTERS 205

I. Simple Bitters, — These are practically free from tannin
and aromatic oils, and include gentian, quassia, calumba, taraxa-
cmn, chirata, pareira, and calendula. The fluid extract and
tincture are the most important preparations.

II. Astringent Bitters, — These contain tannin, which makes
them astringent. Serpentaria, cimicifuga, condurango, and
cascarilla are the chief representatives of this class.

III. Aromatic Bitters, — These contain more volatile oil than
the other classes, and less tannin than the astringent group. The
principal representatives are calamus, aurantii amara cortex,
anthemis, serpentaria, and prunus virginiana.

IV. Compound Bitters, — These are mixtures of simple bitters.
Blending is said to improve their action. Tinctura gentina com-
posita, elixir aromaticum, tincture amara, and vinum aurantii
compositum belong to this class.



XXIU. PHARMACOLOGY OF THE TASTE AND SMELL

The nerves which mediate taste and smell are the first or
Olfactory (L. Oleo — smell; facio — to make) and the ninth or
glossopharyngeal,

Kant defined smell as taste at a distance, taste and smell being
related. The olfactory is a nerve of special sensation and hard to
investigate because its receptive surfaces are intimately associ-
ated with those of the 5th nerve — a nerve of common sensation.
For this reason true smells, or those substances which stimulate
the olfactory only, are hard to separate from pungent substances
like vinegar which also stimulates the 5th nerve.

For the correlation of odor and structure we are indebted
mainly to Georg Cohn (Die Reichstoflfe, 1904) and Zwaarde-
maker (Physiologie des Geruchs, 1895).

Zwaardemaker separates pure odors into nine classes which
have been arranged by Howell (Text Book of Physiology) as
follows:

1. Odores aetherei or ethereal odors, such as are given by
the fruits, which depend upon the presence of ethereal substances
or esters.

2. Odores aromatici or aromatic odors, which are typified by



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206 CHEMICAL PHABMACOLOGY

camphor and citron, bitter almond and the resinous bodies.
This class is divided into five subgroups.

3. Odores fragrantes, the fragrant or balsamic odors, compris-
ing the various flower odors or perfumes. The class falls into
three subgroups.

4. Odore^: ambrosiaci, the ambrosial odors, typified by amber
and musk. This odor is present in the flesh, blood, or excrement
of some animals, being referable in the last instance to the
bile.

5. Odores alliacei or garlic odors, such as are foimd in the
onion, garlic, sulphur, selenimn and tellurium compoimds. These
fall into three subgroups.

6. Odores empyreumatici or the burning odors, the odors given
by roasted coffee, baked bread, tobacco smoke, etc. The odors
of benzene, phenol, and the products of dry distillation of wood
come under this class.

7. Odores hircini or goat odors. The odor of this animal arises
from the caproic and caprylic acid contained in the sweat.
Cheese, sweat, spermatic and vaginal secretions give odors of
similar quality.

8. Odores tetri or repulsive odors, such as are given by many
of the narcotic plants and acanthus.

9. Odores nauseosi or nauseating or fetid odors, such as are
given by feces, by certain plants and the products of putrefaction.

Beaunis classified all substances which affect the olfactory
mucous membranes into three groups (Stewart, Text Book of
Physiology), as follows:

1. Those which act only on the olfactory nerves: (a) Piu-e
scents or perfumes, without pimgency. (6) Odors with a certain
pungency — e,g,y menthol.

2. Substances which act at the same time on olfactory nerves,
and on nervres of common sensation (tactile nerves) — e.gr., acetic
acid.

3. Substances which act only on the nerves of common sensa-
tion (tactile nerves) — e.^. carbon dioxide.

Haller divided odors into:

1. Ambrosial or agreeable.

2. Fetid or disagreeable.

3. Mixed.



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CHEMISTRY OF SMELL 207

And in every day life the division is usually made into:

1. Pleasant, or agreeable.

2. Disgusting, or disagreeable.

CHEMISTRY AND PHYSICS OF ODORS

It was formerly believed that before a substance is recognized
as odoriferous, particles must reach the olfactory nerve through
the air. However, odor may be detected when substances are
dissolved in saline, or in the pharmaceutic waters, and taken into
the nostrils.

The concentration of the substances in the liquid is of some
importance, since cumarin, vaniUin, oil of rose, etc., and other
substances have different odors in strong and dilute solutions.

Practically, however, volatility is the most essential condition
for production of an odor. Since volatilty is mainly dependent
on molecular weight, chemistry plays an important part. In
chemical compounds, it has been found that certain groups or
radicals give rise to rather distinctive odors. These groups are
called the osmophore groups (osmo — odor; phero — to bear).

Two or more osmophore groups may occur in the same sub-
stance. Investigation of these groups has not gone far enough
to classify odoriferous bodies on their chemical groupings. The
modifying influence of associated groups is not yet imderstood.
Hydroxyl, aldehyde, ketone, nitrile, nitro and azoimide groups
are all osmophoric, but may produce pleasant or impleasant
odors, and prediction as to the result is very uncertain. How-
ever, certain facts are established:

1. Homologous derivatives usually have a similar odor.

2. Phenols have characteristic odors.

3. The odor of alcohols is usually pleasant.

4. Unsaturated substances, which are usually chemically
reactive, generally have powerful odors. Triple linked com-
pounds are usually impleasant.

5. If an aldehyde has a pleasant odor, reduction alters the
odor, but does not make it disagreeable.

Drugs that act centrally may stimulate or depress the sensation
of the olfactory nerve; strychnine and cafifeine stinaulate it,
while chloral depresses. Cocaine applied to the nasal mucous



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208 CHEMICAL PHARMACOLOGY

membranes paralyzes the sensation of smell entirely. Marked
changes in the nerve may occur in disease and the sensation of
smell may be entirely abolished (anosmia). Overstimulation
because of the fatigue produced, may also cause this.

Fatigue oif the nerve is quite common. Odors soon give no
sensation when the stimulation is continued, and impleasant odors,
coal gas, etc., by continued action soon lose their effect.

TASTE

Before a substance can stimulate the taste nerves it must be
soluble in the fluids of the paouth. Accordingly as they affect
the taste, sapid substances have been classified as follows:

1. Sweet

2. Bitter

3. Acid

4. SaKne

Regarding the mechanism by which sapid substances stimu-
late the gustatory nerve endings we know but little, but the
stimulus acts on the end organs and not on the nerve trunks.
Nerve trunks in general are not stimulated by any pharma-
cological agent, unless it be applied directly to them; but a sen-
sation of taste is not developed by direct application to the nerve
trunk. Attempts have been made to find a chemical group
responsible for taste, but little progress has yet been made.
Acids and bases owe their characteristic taste to the H, and alka-
Ues to the OH ions.

Sternberg ascribes the bitter taste of alkaloids to their cyclic
constitution, but this assertion will not bear analysis. In the
Mendeljef periodic classification of the elements, the sweet
tasting elements boron, aluminum, scandium, yttrium, lanthanum
are found in the third groups, while lead and cerimn are in the
fourth. Beryllium, another sweet tasting element, is in the
second, while chlorine which often gives rise to sweet compounds
is in the seventh.

The bitter elements — magnesium, zinc, cadmium and mercury
— are found in the second. Sulphur in the sixth group often ^
gives rise to bitter compounds.



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