Are and

F. H. A
mental and be
tile

nickel, vanadium, tin essential for

n3 trace Ph.D.

silicon, man?
M.D. the the hardly Nickel to
with

fluorine, A review12

, and
whose

H. H. Sandstead,4

element

deficiency
unique

in experienvironments

trace body Because

elements, in relatively experimental

even large

though amounts. technology

it is present is out other suggested much of date trace

in

allimais

requires

the of

preparation

of it will

special nutrition. never

. . .

diets
.

can
. .

interest
human

to human
nutritionist.

improved,
rapidly. by the elements,

trace
Thus, time such it

element
this as review

research
may (Pb), as be and

is progressing

is so ubiquitous, the

be

of

concern

Research

is published lead

newer trace elements is of academic interest but of little relevance. Investigators concerned witil tile role of the
newer trace opinions elements from in nutrition often hear

by

Schwarz newer essential Nickel

Until

(4), may have been added trace elements which for man.

to the list of are possibly

Downloaded from ajcn.nutrition.org by guest on August 5, 2013

such other

colleagues or a lack
time

with

interests Such

in of recently,
tilat

aspects may
tilat

of
a

nutrition
short

metabolism. of appreciation
ago zinc deficiency

opinions the fact

reflect to be an nutrition

only

indirect direct

evidence

sug-

was thought far as human then does (2) it has occur as well Today. suines analogs,

esoteric consideration is concerned (1).

tilat zinc

as Since been

gested
living

nickel

has
Now,

a physiological
evidence

role
has been

in

organisms.

been in

established man. Tile Middle States

deficiency has

syndrome
tile

described

in individuals
as from
tile

from

United
villages

States
(3). con-

provided (5-13) indeed essential signs consistent

which silOws that nickel is for some aninlals. Pathological with nickel deficiency have and swine. containing in a trace for 3.5 weeks when 3 to elementshowed com-

Eastern

United

population

been produced in chicks, rats, Day-old chicks fed a diet ng nickel/g and biochemical maintained controlled certain pared They environment

more highly and empty

refined foods, food product calories than in the past.

This
scientists

change

in habits
because of
as

should
an

concern
non-nutritious

nutrition
excessive food
alcoholic

abnormalities

inappropriate,
snack foods,

consumption
items such

relatively
certain

with controls fed 3 pg nickel/g of diet. included a decreased oxygen uptake by in the presence an increase and an increase of a-glyceroin liver total in the liver (13; hepato-

beverages,

and

soft

drinks

individuals,
nutritional place degree. The concern mans plete.
Ilanlely, fluorine

contribute
deficiencies foods

to
when

may, in tile occurrence those to an foods

some of re-

liver homogenates pilOspilate (9-11), lipids (9-11),

conventional trace mineral because, requirenlents This

nickel (F),

inordinate

phospholipid and cholesterol fractions Nielsen, F. 1-I., unpublished observations). Ultrastructural abnormalities in the the

content of such foods is of at present, knowledge of for trace elements is itlconlfor five elements. (V), Silicoll (Si),
recently have

cytes
They rough
of the

were

also

a consistent
dilation of reticulum
The

finding
cisterns and tile
swelling

(9-

11).

included endoplasmic
mitochondria.

of the swelling
of tile

is especially true (Ni), vanadium

and tin (Sn),

which

been cial,

found in the

to diets

be

essential,

or

at

least

berietiIt seems

of laboratory

animals.

probable
essential of this

that

some

of these
has

or beneficial report, silicon

elements are also for man. For tile purpose

been included with

Presented in part at 33rd Annual Meeting of the Institute of Food Technologists, Miami, Florida, June 10-13. 1973. 2 From the USDA, ARS. Human Nutrition Laboratory. P.O. Box D, University Station. Grand Forks, North Dakota 58201. 3Research Chemist. 4Director.

The

American

Journal

of Clinical

Nutrition

27:

NIAY

1974,

pp.515-520.

Printed

in liSA.

515

516 mitochondria matrix of the included pyknotic work by and was cristae. a dilation nuclei. Sunderman deprived was in Other These et the compartment with ultrastructural perinuclear findings al. (12)

NIELSEN of

AND
tile

SANDSTEAD a sparse, rough hair coat. First generation

associated of the

fragmentation changes space in which and earlier they

piglets also grew Thus, nickel major metabolic

in nickel

poorly. appears to abnormalities

have lipid

be

essential. observed
principally
,

Tile so far
in oxida-

extended

deficiency and

occurred have

the
tive

liver.
ability,

Ultramicroscopic
levels

morphology
been liver

found
livers

less severe
of cilicks

ultrastructural
of nickel.

changes

in the

affected.

Also
liver

observed
polysomal

have
profile,

been and

abnormalities
increased

Preliminary studies successive generations

exposed to

(9-I I) were done in of rats. The animals were

throughout fetal, neo-

in the nuclear alkaline

published

deficiency

RNA polymerase, RNase/protein.

No which experimental shows the

increased
has of intake diet (Nielsen, Tile I 1% fat, nickel

active
been

natal,
ently first

and

adult

life.
this

Reproduction
was indicated

was
when

apparseven

evidence level An chick protein,

affected; generation

required

by

experienced
nickel-adequate mortality.

nickel-deficient a 1 5% fetal death

control Fetal mortality dams

female rate, whereas

showed appeared no to

rats six
fetal be

animals to maintain be approximated.

nickel/g for lished contained the experimental rat and 26% observations).

health;

thus,
of is probably F.

this
50

can
to 80

only
ng

adequate

Downloaded from ajcn.nutrition.org by guest on August 5, 2013

H., 47%

unpubdiet carbo-

greater
deficient, a 19% founded a 10% roughly deficient pups of

in
loss

the
second of

second
pups.

generation;
dams finding This

nine
was

nickelcon-

experimental

generation

experienced

by the fact that the eight controls had loss. Loss. in the controls was, however, one-half group. the that observed In all generations dams (age at weaning) stage, had a rougher of the hair in the nickelstudied, the weighed than less did

hydrates, Grains sources concerning

of tilat

and I 6% fiber, minerals, and vitamins. and vegetables appear to be good for dietary nickel (14). Knowledge the chemical form of nickel in foods
origin is limited. in It has been as shown a stable, translocates plants

plant nickel

nickel-deficient

at 4 days and 24 days those from controls. During deficient the pups suckling generally

nickelcoat

anionic organic pounds

they in

amino acid complex (15). Whether Ilickel complexes are the usual comof nickel in plant tissues, and wilether
any way influence the bioavailabiiity of

and
activity litters

appeared
by of second

less
electronic and

active.
third

Measurements
matched deficient generation

of

nickel

remains

to

be

determined.

Decsy

and

monitoring

Sunderman

(16)

have

evidence
in

wilich

suggests
an

and #{235}ontrol sucklings showed that the deficient rats were more lethargic. Nickel deficiency in rats, as in chicks, in changes rats in the were liver. a The muddy livers brown deficient

Ilickelresults of the color

that the nickel preferentially organic complex whicil Nickel acid phytate

metalloprotein, binds nickel which is not

nickeloplasmin, the form of syntllesized,

syntilesized
Grains phytin. phytic the decrease intestinal plant

poorly,
are can (17). in grains the availability absorption. rich fornl Thus,

by

the
a stable it appears other of
contrast

rabbit
are also complex

in
high

or is vivo. in with that nay for of

in nickel

compared with a red the controls. They substructure and were of tile liver exhibited ability in the gradients
tants were

brown color of livers of also ilad a less distinct less friable. Homogenates a reduced oxidative of a-glycerophosphate. rat liver, sucrose density supernain In inand in the with a decrease in monosomes. ilave shown activity

possible vegetables nickel foods

and In of

dietary to origin

in the presence nickel-deficient of and liver

consistent

origin,

foods

animal

contain is data

postmitochondrial increase

relatively little nickel. At present it appears

not a practical problem can be extrapolated to requirement is probably 80 origin iluman prepared bread, ng/g or diet. However, Most diets amount.

that nickel nutriture for man. If animal

polysomes addition, creased increased liver.

an

preliminary nuclear RNA active alkaline

studies polymerase

man, then the dietary in the range of 50 to diets high will in foods provide
of

this
aninlal

RNase/protein

It has been reported recently that deficiency can be produced in swine (5). of the signs include impaired reproduction

nickel Some and

fats, or both, diet containing from butter,

meat,

may be low in nickel. A 7 to 22 ng Ni/g was

nlilk, eggs. refined

white Protein

and

corn

oil

(14).

NEWER

TRACE

ELEMENTS

517

supplied
43.5%, conceivably

I 7.4%
and fat be

of
of

the
concern

calories,
Nickel in

carbohydrate
nutriture individuals may with stress.

only

28

days,
levels

significantly
occurred

increased
(24; Nielsen,

plasma
F. H.,

39.1%.

cholesterol

diseases
or who

that
are

interfere
under

with
extreme

intestinal
physiological

absorption in plasma
of the liver

unpublished observations). (25, 26) indicate that plasma

are also significantly chicks. increased

Other
in

recent

data
levels

triglyceride

vanadium-

It is known
decreased

that

the

level
with

of nickel
cirrhosis

is

deficient

in patients

In rats,
by
were

reproductive

with findings Another

or concentrations

cllrOnic uremia are indicative consideration

of

(18). Perilaps, these of nickel depletion. is the relatively high

in sweat (49 pg/liter)

vanadium

deprivation

fourth
cantly

generation
significantly

performance is impaired (25, 26). Wilen five, female rats were mated, there
fewer

nickel

more

deaths

live of neonatal controls.

births and signifipups than with

(19). sweat
nickel.

Conditions which may conceivably

Thus, studies whether are

result in large increase tile

needed to

losses of need for

define the

vanadium-sufficient

Vanadium
on bone

deficiency
development

also
in

has adverse the cilick

effects (24).
chick

level
ascertain

of

nickel

required
nickel

by

man,

and
occurs

to

deficiency

Histologically tibia shows

the epiphysis.

,
severe

the The

vanadium-deficient cells appear compressed

disorganization These
thickened distribution
of

of tile cells abnormalities

leg of SO4 structure. and

of

Downloaded from ajcn.nutrition.org by guest on August 5, 2013

naturally.

and

their
result

nuclei
in uptake
to

flattened.
and
those

a shortened,

Vanadium Data
essential

The

supporting
element for

the view
animals

that
was

vanadium
first

is an
reported

hexosamine
similar

concentrations
the

in the
controls. deficiency.

epiphysis
It

are
seems,

by Hopkins finding was

and Mohr a significantly

(20,

21). reduced

Tile initial growth of

therefore,
is not affected

that data
two

mucopoiysaccharide
by vanadium

metabolism laboratories
established for higher

wing and tail feathers containing less than 10 then, several additional attributable to low levels have been reported in rats Strasia (22) found that
ng vanadium/g of diet

in cilicks fed a diet ng vanadium/g. Since deficiency symptoms of dietary vanadium and chicks. rats fed less than 100
reduced body

These
and that animals. on

from
different

four

different
have nutrient

species

vanadium

is an essential

Due required
can of

to limited data, the level of vanadium by rats and chicks to maintain health
100
witil

exhibited

growth

and

significantly

increased

blood

only be estimated. approximately adequate of 26%

It appears ng/g
an

that for fat,

an intake chicks is diet and 57%

packed cell volume when compared with controls receiving at least 0.5 pg vanadiuin/g. He also noted an increase in blood and bone iron in deficient rats. Schwarz and Mime (23) found that rats fed a highly purified amino acid diet (containing dium) demonstrated an unknown a growth amount response of vanato 50 to

probably composed carbohydrate non-nutritive observations). vanadium This accurately Soremark activation 0.1 pears coiltains liver, fish, Schroeder is

experimental

protein,

6%

(balance minerals, vitamins, and fiber) (Nielsen, F. H.. unpublished Information in natural feeds in part due for to low analyzing as to the and foods the levels values range amount of is limited. in by than

difficulty of vanadium. obtained from less

100
require

ng vanadium/g
more than

of diet.
30 to 35 at
to was have

Chicks
tilat

apparently
as

ng vanadium/g

depressed (Nielsen,
Vanadium metabolism.

growtil occurs F. H., unpublished

appears It

dietary
a role

level
in lipid that

(27) reported analysis. Tilese in ng/g than in

data).
tound

vanadiuin/g to 52 less

peas, beets, radishes. ng/g contain found

carrots, and Milk generally basis) and

(20. decreased of age.

21)

0.1

(fresh

vanadium-deficient levels of cholesterol days were a diet their greater based plasma than on

chicks Ilad at 28 days

plasma but at 49

and meat et al. (28)

up to 1 0 ng/g. few foods rich in

cholesterol concentrations tilose of control chicks. With peanut meal-sucrose-lard similarly were found whereas after

vanadium.
nuts, These items limited contain

They

include
oils. and

bread,
a few

some
root

graitls
vegetables.

and

vegetable

containing decreased as early as

30 to 35 ng vanadium/g. plasma cholesterol levels 14 days of deficiency,

data indicate that many dietary amounts of vanadium which are

many additional data are needed

below

100 ng/g.

Obviously,

518

NIELSEN

AND

SANDSTEAD

before firm conclusions can be drawn; but, if man has a vanadium requirement which is similar to that of rats and chicks, adequate vanadium nutrition should not be taken for granted. A diet exclusively of milk, meat, and certain vegetables could contain less than 100 ngV/g. Silicon
Silicon is one of the newest elements to be

pg/g) were found in chondroitin 6-sulfate, heparin, and keratan sulfate-2 from cartilage. Hyaluronic acid from vitreous humor and keratan sulfate-i from cornea were silicon-free. Schwarz concluded from various biochemical studies that silicon is present as a silanolate, i.e.,
an ether (or ester-like) derivative of silicic acid,

and

postulated that silicon in the glycosaminoglycans Silicon may link portions

charides rides to to each proteins. other, Thus,

has a structural role and polyuronides. of the sane polysacnlucopoiysacchasuggested that and

or acid Schwarz

shown reported
early chicks.

essential (29, 30)

stage The Chicks of first fed growth.

for animals. It was first that silicon is necessary for an

bone clear calcification evidence that in rats silicon and is

silicon agent
resilience

may function as a biological and may contribute to the

ofconnective tissue.

crosslinking
structure

essential
32). depressed

for animals
a

was
Pallor had

reported
of the

in 1972
diet legs,

(31,
had comb,

It

was

estimated
tilat

(Carlisle,
the chick

E.

M.,

personal
for

Downloaded from ajcn.nutrition.org by guest on August 5, 2013

silicon-deficient

communication)

requirement

skin,

and

mucous
tissue

membranes
a muddy

occurred.

The subcucontrol

silicon as sodium to 200 pg/g of 26% amino acids,

silicate is in the range of 100 experinlental diet contaitling 5% fat, 62% carbohydrate.

subcutaneous

to yellowish

color in contrast taneous tissue of

animals. Tile and their comb was ering was retarded.

to the white-pinkish the silicon-adequate

chicks had no a severely attenuated. Leg bones had

deficient

wattles Feaththinner

cortex ference
and

and were shorter and of smaller than were those of controls.

tibias fractured more easily, cranial

circumFemurs
bones

and 7% minerals and vitamins. It is probable that other forms of silicon are more available than the silicate. Thus, the absolute requirement probably is lower than 100 to 200 pg/g. Foods high in silicon include unrefined grains
such as unpolished rice. solution For of tilose silicon who drink

their
is a

calories,
saturated

it should

be reassuring pg/g. skin

that
containing

beer of are

were These
suggestion aspect

flatter, latter
of bone

and gross
that

beaks signs
silicon

were more flexible. supported the earlier

is involved in some

approximately 1,200 animal origin, except relatively low in silicon. Fluorine A beneficial known since
discovered significant in treating that role patients of effects

Dietary items (i.e., chicken)

calcification. found (33) that silicon in depressed growth deficiency and skull

It also was in rats results defo rmatiOlls.

More
the matrix. and spongiosae, hexosamines. A that role

recently,
In tile

it has
silicon-deficient

been
involve

shown
the
chick

(34)
metatarsus

that

function the late

of fluorine has been 1930s when it was

can of reported osteoporosis with may
bone

skeletal tibial

alterations epiphyses, there for is silicon

cartilage and

the fluoride iOtl in tile prevention suffering sodium upon from

play human that

epipilyseal a significant in

plates, decrease

dental caries. In the 1960s, it was

and
mucopolysaccharide tial

other
amounts calcium

demineralizing

diseases
fluoride back pain, Epidemiological

substanresult in
deilsity.

metabolism
silicon minoglycans apparently (35). bound from
dermatan

is further
and bound (35) of siiicon/g umbilical
sulfate.

supported
of

by
certain

tile

finding
glycosait is matrix pg of

beneficial and

is a constituent

balance.

studies

polyuronides where to the polysaccharide reported 330 to 554

have

shown

that
in some areas.

there

is

substantially
areas than

less
in is not teeth.

osteoporosis low-fluoride only beneficial but also skeleton have essential a beneficial been

iligh-fluoride

Schwarz the

purified ilyaluronic acid cord, chondroitin 4-sulfate,

alld heparan sulfate. These

Apparently, fluorine for the maintenance of of effects as one and

for tile mailltetlance in the adult. Tllese reviewed element effect were n by defined health

a nornlai of tluorirte (36). which well-being. If an has

levels 50,000 280

correspond to repeating 85,000 units.

to

1 atom Lesser amounts

of weight

silicon or (57 130

to

per to

Underwood

molecular

191

NEWER

TRACE

ELEMENTS

519

usual conditions in which individuals in the light of the above evidence, fluorine would be considered an essential element in human nutrition. Recently, interest in fluorine has been stimulated by unconfirmed reports that fluorine may be necessary for normal hematocrit levels, fertility, and growth. It has been found that during the stress of pregnancy, feeding
diets low hematocrits fertility litters females in fluoride in mice by reduced, may (37). occurs first but and result Also, (38). litter second size in decreased a decrease The number generation was not in of

under the live, then

element has been considered an environmental contaminant instead of a possible essential dietary factor. In 1970. it was reported that tin
is essential for the growtll of rats maintained on

apparently produced was

affected.
addition Although an unusual

Tile

condition

was

prevented
drinking for man, to rodents.

by

the

of 50 pg fluorine/mI this amount is toxic amount to be fed

water. it is not

purified amino acid diets in a trace elementcontrolled environment (40). Rats required I pg tin as stannic sulfate per gram of experimental diet for optimal growth. This observation ilas not been confirmed. Tin has a number of chemical properties tilat offer possibilities for biological function. Tetravalent tin has a strong tendency to form coordination complexes with 4, 5, 6, and possibly 8 ligands. Thus, it has been suggested (40) that tin may contribute to the tertiary structure of proteins or other components of biological importance. It also has been speculated (40) tilat tin may participate in oxidationreduction reactions tile in

Downloaded from ajcn.nutrition.org by guest on August 5, 2013

It also stimulates
purified

has the
aniino must,

been growth
acid until
for

reported of rats
diet and

tllat fed

fluorine highly
in

biological

systems

be-

maintained

trace
observation
with

element-controlled
reservation

isolators
confirmed,

(39).
be

This
viewed

the

following

reasons:

I)
even F. 2)

Sn2=Sn4 potential of 0.13 volts is witilin tile physiological range. In fact, it is near the oxidation-reduction potential of flavine enzymes. The levels of tin reported to promote growth
in rats are similar to the amounts found in

cause

The though

control they between

rats were the

grew suboptimally, supplemented with the differences deficient and the

many

foods

of plant

and

animal

origin

(40).

Although
gain

significant. were small,

in weight
control

Summary 26 Three
silicon)

animals
days,
essential

approximately
the diet including been colltained V. Si, able they to have

6 g over

new
have

elements
been

(nickel,
found

vanadium,
and

and
two

even have

though
elemetlts

all known and Sn. 3) confirm fed

this

essential

Others finding

not

(fluorine To date,
essential it seems

and tin) possibly these elements

for man. However, that probable

essential have not

from they have

for animals. been shown

animal an data, essential

even

though

diets

containing less fluorine (36). Clearly more research will be necessary before it can be stated tilat fluorine is essential

function

in human

nutrition

and

metabolism.

At present.
be estimated.

a requirement
However,

for growth. for fluorine cannot

of diet (39)

U
References
I. 2. SANDSTEAD H. H. Zinc nutrition in the United States. Am. J. Clin. Nutr. 26: 1251, 1973. IIAMBIDGE, K. M., C. HAMBIDGE, M. JACOBS AND J. D. BAUM. Low levels of zinc in hair, anorexia, poor growth and hypogeusia in children. Pediatr. Res. 6: 868, 1972. SANDSTFAD. II. 11., A. S. PRASAI). A. R. SCHULERT. Z. FARID. A. MIALE, JR., S. BASSILLY AND W. J. DARBY. Human zinc

I to 2 pg/g

appears include
pg/g).

beneficial. sea foods

Cereal and

Foods high (5 to 10 pg/g)

other grains

in fluorine and tea (100

I to 3

contain

pg/g. (dry
above

Cows basis)

milk (36).

usually An

contains important
On in

I to 2 pg/g source of
the basis of the animals and
3.

fluorine

is drinking experimental

water. studies

studies in man witil osteoporosis, it seems possible that fluoridation of city water supplies is beneficial tion of caries. in
ways

deficiency,
to treatment.

endocrine
Am.

manifesta

lions and response

other

than

in the

preven-

4.

Tin
Trace amounts of and dietary items, tin occur in many tissues but until recently, the
5.

J. Clin. Nutr. 20: 422, 1967. SCHWARZ. K. New essential trace elements (Sn, V. I, Si): progress report and outlook. Presented at the Second International Symposium on Trace Element Metabolism in Animals, Madison, Wisconsin, June 18 - 22, 1973. ANKE. M., M. GRUN, G. DITTRICH, B. GROPPEL AND A. HENNIG. Low nickel rations

520 for growth and reproduction In 1973.

NIELSEN

AND

SANDSTEAD 21.
AND H. E. MOHR. Effect on plasma cholesterol of chicks. Federation Proc. 30: 462, 1971 (abstr.). STRASIA. C. A. Vanadium: essentiality and toxicity in the laboratory rat. Ph.D. Thesis. Ann Arbor, Michigan. University Microfilms, 1971. SCHWARZ, K., AND D. B. MILNE. Growth effects of vanadium in the rat. Science 174: 426, of vanadium deficiency 1971.

the

Second

International

Element consin,

NIetabolism June 18-22,

in pigs. Presented at Symposium on Trace Animals, Madison, \Vis-

HOPKINS,

L. L., JR.,

22.

6. NIELSEN,
Evidence of

F. Proc. F.

H., Soc. H.,

AND Exptl. AND

H.

F. Biol.

SAUBERLICH.
for nickel by

a possible

requirement

the chick. 1970. 7. NIELSEN,

studies Trace

Med.

134:

845,

23.

D.

J. HIGGS.

Further
In:

involving Substances

a nickel deficiency in Environmental

in chicks. Health-IV,

24.

NIELSEN, F. H., AND D. A. OLLERICH. Studies on a vanadium deficiency in chicks. Federation

Proc. 32: 929, 1973 (abstr.). HOPKINS, L. L., JR., AND H. F. MOHR. Vanadium as an essential element. Federation Proc. June 1974. HOPKINS, L. L., JR. Fssentiality and function vanadium. In: Trace Element Metabolism Animals-2, edited by NV. G. Hoekstra, J. Suttie, H. F. Ganther and W. Mertz. Baltimore, Maryland: University Park. In press. SOREMARK, R. Vanadium in some biological specimens. J. Nutr. 92: 183, 1967. SCHROEDER, H. A., J. J. BALASSA AND I. TIPTON. Abnormal trace metals in man-vana-

8.

9.

10.

p. 241. NIELSEN, I-. H. Studies on the essentiality of nickel. In: Newer Trace Elements in Nutrition, edited by W. Mertz and \V. F. Cornatzer. New York: Marcel Dekker, 1971, p. 215. NIELSEN. F. H., AND D. A. OLLERICH. Nickel: a new essential trace element. Federation Proc. June 1974. NIELSEN. F. H. Essentiality and function of nickel. In: Trace Element Metabolism in Animals-2, edited by W. G. Hoekstra, J. W. Suttie,

edited by D. D. Hemphill. Univ. Missouri Press, 1971.

Columbia,

Missouri:
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26.

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27. 28.

H.

H. F. Ganther
land: University

and
Park.

W. Mertz.
In press.

Baltimore, OLLERICH,

MaryG.
J. 29. 30.

dium. bone

J. Chronic
F. F.

Diseases
M. M. Silicon:

16: 1047,
a possible

1963.
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11.

NIELSEN,

F.

H.,

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