MEDICINE AND SURGERY "F"
Course of LABORATORY MEDICINE
Hypervitaminoses and hypovitaminoses

VITAMINS AND OTHER ESSENTIAL NUTRIENTS: EXCESS AND DEFICIENCY

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      Insufficient dietary apport of vitamins and other essential nutrients (essential aminoacids, essential fatty acids, etc.) may be at the origin of disease. The elderly are at special risk, as are some fragile patients (e.g. onchological patients under chemotherapeutic treatment). Deficiency conditions may be in some cases observed because of reduced absorption, the typical example is avitaminosis B12 in patients suffering of atrophic gastritis or having undergone gastric surgery. Hypervitaminoses are observed for lipid soluble vitamins which are physiologically stored in our organism (usually in the liver), and are usually the result of excessive dietary supplementation: thus they are iatrogenic diseases. Vitamins and essential nutrients are many and the diseases due to their insufficient apport are difficut to diagnose; however, provided that the physician asks for the appropriate analysis, the laboratory can determine the concentration of all or almost all these substances and identify the selective deficit.

vitamin and its biological functionrecommended daily allowancedeficiency diseasenormal serum concentration
A (retinol)
vision, epitelium differentiation
0.5 - 1 mgreduced vision at dusk, skin and mucosal lesions20 - 50 μg/dL
D (calciferols)
calcium absorption
10 μgricketts, osteomalacia25 - 40 ng/mL of 25-hydroxy D3
E
antioxidant
3 - 10 mgoxidative damage of tissues; anemia>0.8 mg/dL
K
cofactor of carboxylation of Glu in coagulation enzymes
produced by intestinal microbiota
(deficiency may be simulated by
warfarin-like anticoagulants)
hemorragic syndrome- (measure PT, PTT)
Lipoic acid
cofactor of acyl transferases
- (deficiency uncommon)
B1 (thiamine)
cofactor of carboxylases
0.3-1.5 mgneurological symptoms (Beri-Beri,
Wernicke-Korsakoff syndrome)
- (urinary excretion >50 μg/day)
B2 (riboflavin)
precursor of FAD
0.5-2 mgskin and mucosal lesions, anemia- (urinary excretion >30 μg/day)
B3 (niacin, nicotinic acid)
precursor of NAD and NADP
6-20 mgpellagraurinary N-methylnicotinamide and pyridone < 1.5 mg in 24 hours
B5, W (pantothenic acid)
precursor of CoA-SH
B6 (pyridoxine)
cofactor of transaminases
0.5-2 mganemia, neuropathy-
B8, H (biotin)
cofactor of carboxylases
- (deficit uncommon)
B9 (folic acid)
cofactor of methyl-transferases and some redox reactions
30-400 μgmegaloblastic megalocytic anemia6-15 ng/mL
B12 (cobalamine)
cofactor of methyl-transferases
0.5-3 μgmegaloblastic megalocytic anemia
(pernicious anemia, Brill's disease)
>200 pg/mL
C (ascorbic acid)
redox cofactor
necessary for the biosynthesis of OH-Pro and OH-Lys in collagen
50 mgscurvy- (>0.1 mg/dL in the leukocyte / platelet fraction)


      Diagnosis of hypovitaminoses
      As a general rule hypovitaminoses cause diseases with quite uncharacteristic symptoms, thus their diagnosis is difficult. Exceptions to this rule are the macrocytic megaloblastic anemias of folate and B12 deficiency, ricketts, scurvy, and the hemorragic syndrome due to antivitamins K.

      Possible common symptoms of avitaminosis: in the majority of vitamin deficiencies the target organs are: (i) the skin and mucosae, which may present degenerative lesions and ulcerations; (ii) the central and peripheral nervous systems; (iii) the blood (anemia) and vessels (hemorragic syndromes); (Iv) the gastro-intestinal tract. With the exception of the nervous system, these organs have rapid cell turnover:
- skin lesions (deficiency of vitamins B2, B3, A)
- anemias (deficiency of vitamins E, B2, B9, B12)
- neurological symptoms (deficiency of vitamins B1, B2, B3, B6, B12)

      Conditions that favor hypovitaminoses are:
- major catastrophes (famines, civil ware, refugees, etc.)
- increased requirement (e.g. folate during pregnancy)
- prolonged antibiotic therapy, which destroys the vitamin-producing intestinal bacterial flora
- malnutrition and malabsorption (e.g. etilism and Wernicke syndrome; athropic gastritis and pernicious anemia)
- reduced endogenous prodction for those vitamins that are partly produced by our body (e.g. nicotinamide and defects of Trp metabolism of Hartnup disease; ricketts due to insfficient exposure to sunlight; antibiotic therapy and vitamin K)
- assumption of antivitamins (warfarin anticoagulants and vitamin K; antibacterial and antiparasitic drugs acting as folate antagonists like trimetoprim)

      Laboratory diagnosis of avitaminoses. Measuring the concentration of vitamins in the serum, blood or urine is feasible; often the effects of vitamin deficiency can also be quantitatively assessed (e.g. coagulation defects in the case of assumption of antivitamin K; anemias; etc.), but these are rarely characteristic enough to warrant a diagnosis. The risk should be consiedere that a patient may suffer of deficiency of multiple vitamins. If the patient is at risk for malnutrition and presents cutaneous, neurological or blood-related symptoms, administration of a multivitamin preparation is advisable, because the contraindications to this therapy are virtually non-existent. A very special case to consider, however, is pernicious anemia.

      Hypovitaminoses are rarely observed in the absence of specific risk factors, which include: (i) social emergency conditions (civil wars, refugees, etc.); (ii) old age or assumption of chemotherapy (these conditions may reduce appetite, and cause malnutrition); (iii) chronic intestinal diseases causing malabsorption; (iv) very special dietary habits (e.g. veganism and hypovitaminosis B12; use of white rice and Beri-Beri). By contrast, the "classical hypovitaminoses", which were historically observed in whole populations or groups (e.g. scurvy, pellagra, ricketts, etc.), due to poor diets are nowadays uncommon.

      Pellagra (vitamin B3 deficiency) was formerly common in Italy, especially in the Veneto region, due to unbalanced (poor) nutrition, based on maize porridge (polenta). Maize does contain vitamin B3 (niacin, nicotinamide), but special tretaments are required to make it available for non-ruminant mammals (nixtamalization: cooking followed by tretament with alkali). The symptoms of the disease are cutaneous, intestinal and neurological (the 3 Ds: dermatitis, diarrhoea, and dementia). Pellagra is lethal if untreated. Vitaminn B3 is abundant in many fresh vegetables and in milk, and can be produced by the metabolism of tryptophan. The diagnosis is difficult because of the aspecific nature of the symptoms, especially cutaneous; notice that sun exposure exacerbates the dermatitis, evebn though non-exposed areas are affected as well. Serum levels of Trp, nicotinamide, NADH and NADPH are reduced; however, of greater diagnostic relevance is the reduced urinary escretion of metabolytes N- methylnicotinamide and pyridone: less than 1.5 mg in 24 hours suggests niacin deficiency. It is also important to exclude other possible causes of dermatitis (e.g. autoimmune).

      Pernicious anemia (Brill's disease) is a potentially lethal disease caused by the deficiency of vitamin B12. This vitamin has a very low recommended daily intake, and is present mostly in food of animal origin. Every "common" diet contains a sufficient amount of this vitamin. The chemical structure of the vitamin is complex and intestinal absorption is mediated by binding to a specific transport protein produced by the gastric mucosa and called the "intrinsic factor". The complex of vitamin B12 and the intrinsic factor is absorbed by the gut via receptor-mediated endocytosis; a reservoir of vitamin B12 is stored in the liver.
      Pernicious anemia is only observed in some very special cases, including (i) patients suffering of athropic gastritis, gastric cancer, or having undergone to surgical resection of the stomach (e.g. because of cancer); these patients do not produce the intrinsic factor. (ii) Strictly vegan patients who refuse every food of animal origin, and do not make use of vitamin B12 supplementation. (iii) Newborns of mothers in the two above conditions (these babies may present congenital permanent neurological lesions).
      Oral supplementation of vitamin B12 is effective in case (ii), but not in case (i), where intramuscular administration is necessary.
      Diagnosis relies on the association of neurological symptoms and macrocytic anemia; a risk condition is always present. Confirmation is by determination of vitamin B12 concentration in the serum by radioimmunoassay, and by the Schilling test (measurement of the urinary excretion of radiolabeled vitamin B12). The intrinsic factor can be measured in gastric secretions. Achloridria is common but not diagnostic. Differential diagnosis is relatively easy because the possible causes of macrocytic anemia are limited: besides vitamin B12 deficiency they include folate deficiency, copper deficiency and, possibly, scurvy.

      Folate deficiency may be observed in pregnancy, due to the large demand of this vitamin by the fetus. Dietary supplementation with folate tablets during pregnancy is recommended.

      Hypervitaminoses
      Diseases due to excess vitamin supply are iatrogenic and due to the patient taking excess vitamin supplementation. No normal diet can cause hypervitaminoses. Moreover, the majority of water-soluble vitamins are not stored in our body and thus any excess is disposed of by the kidney; in practice only liposolube vitamins (A, D, E, and K) are physiologically stored in the liver and can cause hypervitaminoses.

Clinical examples
1) 85 year old patient complaining of malaise and muscular weakness. Physical examination reveals: petechiae, loss of some teeth. Blood test reveals:
hemoglobin9 g/dL *
erythrocyte count3 x 106 /mmc *
mean corpuscular volume75 fL (normal value 80-100 fL)*
white cell count8 x 103 /mmc
platelets220 x 103 /mmc
Analysis of the case: the main symptoms in this case are microcytic anemia (reduced MCV), loss of teeth, and petechiae. Microcytic anemia may be due to several causes, e.g. vitamin C deficiency, thalassemia minor, or iron deficiency. Loss of teeth and petechiae in a patient having normal platelet count suggest scurvy. Inquire for nutritional habits; prescribe vitamin C tablets; measure serum iron and transferrin; sequence the genes of hemoglobin subunits.

2) 45 year old patient complaining of chronic arthritis, treated with antiinflammatory drugs and methotrexate. Physical examination reveals obesity, chronic arthritis. Blood test reveals:
hemoglobin12 g/dL *
erythrocyte count3.8 x 106 /mmc *
mean corpuscular volume105 fL (normal value 80-100 fL)*
white cell count8.3 x 103 /mmc
platelets180 x 103 /mmc
Analysis of the case: in addition to arthritis the patient has macrocytic anemia. Macrocytic anemia may be due to deficiency of vitamin B12 or folic acid, or to hypothyroidism. Folate deficiency may be due to methotrexate, which is an antifolic agent. There is no obvious indication that absorption of vitamin B12 may be reduced. Measure folic acid in the serum. Carry out a complete thyroid investigation (measure T3, T4, TSH, and basal metabolism).

Questions and exercises:
1) Macrocytic and macroblastic anemia is observed in:
deficiency of folate or vitamin B6
deficiency of folate or vitamin B12
deficiency of vitamin B6 or B12

2) The normal blood concentration of vitamin A is:
150-750 pg/mL
25 - 40 ng/dL
20 - 50 μg/dL

3) Some vitamins can be produced in our body:
B6 from Trp; D from ergosterol; K by the intestinal microfauna
B12 from the heme; A from unsaturated fatty acids
C from glucuronic acid; panthetein from Cys

4) Wernicke neurological syndrome is due to a deficiency of:
vitamin B1
vitamin B2
vitamin B6

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Thank you Professor (lecture on bilirubin and jaundice).

The fourth recorded part, the one on hyper and hypoglycemias is not working.
Bellelli: I checked and in my computer it seems to work. Can you better specify
the problem you observe?

This Presentation (electrolytes and blood pH) feels longer than previous lectures
Bellelli: it is indeed. Some subjects require more information than others. I was
thinking of splitting it in two nest year.

Bellelli in response to a question raised by email: when we compare the blood pH
with the standard pH we do not mean to compare the "normal" blood pH (7.4)
with the standard pH. Rather we compare the actual blood pH of the patient, with
the pH of the same blood sample equilibrated under standard conditions.
Thus, if we say that standard pH is lower than pH we mean that equilibriation with
40 mmHg CO2 has caused absorption of CO2 and has lowered the pH with respect
to its value before equilibration.

(Lipoproteins) Is the production of leptin an indirect cause of type 2 diabetes since
it works as a stimulus to have more adipose tissue that produces hormones?
Bellelli: in a sense yes, sustained increase of leptin causes the hypothalamus to adapt
and to stop responding. Obesity ensues and this in turn may cause an increase in the
production of resistin and other insulin-suppressing protein hormones produced by the
adipose tissue. However, this is quite an indirect link, and most probably other factors
contribute as well.

(Urea cycle) what is the meaning of "dissimilatory pathway"?
Bellelli: a dissimilatory pathway is a catabolic pathway whose function is not to produce
energy, but to produce some terminal metabolyte that must be excreted. Dissimilatory
pathways are necessary for those metabolytes that cannot be excreted as such by the
kidney or the liver because they are toxic or poorly soluble. Examples of metabolytes
that require transformation before being eliminated are heme-bilirubin, ammonia,
sulfur and nitrogen oxides, etc.

Talking about IDDM linked neuropathy can be the C peptide absence considered a cause of it??
Bellelli: The C peptide released during the maturation of insulin, besides being an indicator
of the severity of diabetes, plays some incompletely understood physiological roles. For
example it has been hypothesized that it may play a role in the reparation of the
atherosclerotic damage of the small arteries. Thus said, I am not aware that it plays a direct
role in preventing diabetic polyneuropathy. Diabetic neuropathy has at least two causes: the
microvascular damage of the arteries of the nerve (the vasa nervorum), and a direct
effect of hyperglycemia and decreased and irregular insulin supply on the nerve metabolism.
Diabetic neuropathy is observed in both IDDM and NIDDM, and requires several years to
develop. Since the levels of the C peptide differ in IDDM and NIDDM, this would suggest
that the role of the C peptide in diabetic neuropathy is not a major one. If you do have
better information please share it on this site!

In acute intermitted porphyria and congenital erythropoietic porphyria why do the end product
of the affected enzymes accumulate instead of their substrate??
Bellelli: First of all, congratulations! This is an excellent question.
Remember that a condition is which the heme is not produced is lethal in the foetus; thus
the affected enzyme(s) must maintain some functionality for the patient
to be born and to come to medical attention. All known genetic defects of heme
biosynthesis derange but do not block this metabolic pathway.
Congenital Erythropoietc Porphyria (CEP) is a genetic defect of uroporphyrinogen
III cosynthase. This protein associates to uroporphyrinogen synthase (which is present
and functional in CEP) and guarantees that the appropriate uroporphyrinogen isomer is produced
(i.e. uroporphyrinogen III). In the absence of a functional uroporphyrinogen III
cosynthase other possible isomers of uroporphyrinogen are produced together with
uroporpyrinogen III, mostly uroporphyrinogen I. The isomers of uroporphyrinogen
that are produced differ because of the positions of propionate and acetate side chains,
and this in turn is due to the pseudo symmetric structure of porphobilinogen. Only
isomer III can be further used to produce protoporphyrin IX. Thus in the
case of CEP we observe accumulation of abnormal uroporphyrinogen derivatives, which, as
you correctly observed are the products of the enzymatic synthesis operated by
uroporphyrinogen synthase.
The case of Acute Intermittent Porphyria (AIP) is similar, although there may be variants
of this disease. What happens is that either the affected enzyme is a variant that does not
properly associate with uroporphyrinogen III cosynthase or presents active site mutations
that impair the proper alignement of the phoprphobilinogen substrates. In either case
abnormal isomers of uroporphyrinogen are produced, as in CEP.
Also remark that in both AIP and CEP we observe accumulation of the porphobilinogen
precursor: this is because the overall efficiency of the biosynthesis of uroporphyrinogens is
reduced. Thus: (i) less uroporphyrinogen is produced, and (ii) only a fraction of the
uroporphyrinogen that is produced is the correct isomer (uroporphyrinogen III).


is it possible to take gulonolactone oxidase to synthesize vitamin C
instead of vitamin C supplement?
Bellelli: no, this approach does not work. The main reason is that
the biosynthesis of vitamin C, as almost all other metabolic processes, occurs intracellularly.
If you administer the enzyme it will at most reach the extracellular fluid but will not be
transported inside the cells to any significant extent. Besides, there are other problems
in this type of therapy (e.g. the enzyme if administered orally, may be degraded by digestive
proteases; if administered parenterally, may cause the immune system to react against a
non-self protein). In theory one could think of a genetic modification of the inactive human
gene of gulonolactone oxidase, but the risk and cost of this intervention would not be
justified. In addition to these considerations, except for cases of shipwreckage or
other catastrophes, a proper diet or administration of tablets of vitamin C is effective,
risk-free and unexpensive, thus no alternative therapy is reasonable. However, I express my
congratulations for your search on the biosynthesis pathway of ascorbic acid.


Resorption and not reabsorption would lead to hypercalcemia ie bone matrix being broken down.
Bellelli: I am not sure to interpret your question correctly. Resorption indicates destruction of the bone matrix and release of calcium and
phosphate in the blood, thus it causes an increase of calcemia. Reabsorption usually means active transport of calcium from the renal tubuli to the blood, thus
it prevents calcium loss. It prevents hypocalcemia, and thus complement bone resorption. To avoid confusion it is better use the terms "bone resorption" and "
renal reabsorption of calcium". If you have a defect in renal reabsorption, parthyroid hormone will be released to maintain a normal calcium level by means of
bone resorption; the drawback is osteoporosis.

In Reed and Frost model: I haven't understood what is the relationship
between K and R reproductive index. Thank you Professor!
Bellelli: in the Reed and Frost model K is the theoretical upper limit of
R0. R the reproductive index is the ratio (new cases)/(old cases) measured after
one serial generation time. R0 is the value of R one measures at the beginning
of the epidemics, when in principle all the population is susceptible.

What is the link between nucleotide metabolism and immunodeficiencies and mental retardation?
Bellelli: the links may be quite complex, but the principal ones are as follows:
1) the immune response requires a replication burst of granulocytes and lymphocytes, which in turn requires
a sudden increase of nucleotide production, necessary for DNA replication. Defects of nucleotide metabolism
impair this phase of the immune defense. Notice that the mechanism is similar to the one responsible of
anemia which requires a sustained biosynthesis of nucleotides at a constant rate, rather than in a burst.
2) Mental retardation is mainly due to the accumulation of nulceotide precursors in the brain of the
newborn, due to the incompletely competent blood-brain barrier.

How can ornithine transaminase defects cause hyperammonemia? Is it due to the accumulation
of ornithine that blocks the urea cycle or for other reasons?
Bellelli: ornithine transaminase is required for the reversible interconversion of ornithine
and proline, and thus participates to both the biosynthesis and degradation of ornithine. The enzyme is
synthesized in the cytoplasm and imported in the mitochondrion. Depending on the metabolic conditions
the deficiency of this enzyme may cause both excess (when degradation would be necessary) or defect
(when biosynthesis would be necessary) of ornithine; in the latter case, the urea cycle slows down. Thus
there is the paradoxical condition in which alternation may occur between episodes of hyperammonemia
and of hyperornithinemia.

When we use the Berthelot's reaction to measure BUN do we also have to
measure the concentration of free ammonia before adding urease?
Bellelli: yes, in principle you should. Berthelot's reaction detects ammonia,
thus one should take two identical volumes of serum, use one to measure free ammonia,
the other to add urease and measure free ammonia plus ammonia released by urea. BUN is
obtained by difference. However, free ammonia in our blood is so much lower than urea that
you may omit the first sample, if you only want to measure BUN.

Why do we have abnormal electrolytes in hematological neoplasia e.g.
leukemia?
Bellelli: I do not have a good explanation for this effect, which may have
multiple causes. However, you should consider two factors: (i) acute leukemias cause a massive
proliferation of leukocytes (or lymphocytes depending on the cell type affected) with a very
shortened lifetime; thus you observe an excess death rate of the neoplastic cells. The dying
cells release in the bloodstream their content, which has an electrolyte composition different
from that of plasma: the cell cytoplasm is rich in K and poor in Na, thus causing hyperkalemia.
(ii) the kidney may be affected by the accumulation of neoplastic white cells or their lytic products.

Gaussian curve: If it is bimodal is it more likely to be a "certain diagnosis" than if it is
unimodal or does it only show the distinguishment from health?
Bellelli an obviously bimodal Gaussian curve indicates that the disease is clearly
separated from health: usually it is a matter of how precise and clear-cut is the definition of the disease.
For example tuberculosis is the disease caused by M. tuberculosis, thus if the culture of the sputum is
positive for this bacterium you have a "certain" diagnosis (caution: the patient may suffer of two diseases,
e.g. tuberculosis and COPD diagnosis of the first does not exclude the second). However, in order to have
a "certain" diagnosis it is not enough that distribution of the parameter is bimodal, it is also required that the
patient's parameter is out of the range of the healthy condition: this is because a distribution can be
bimodal even though it is composed by two Gaussians that present a large overlap, and the patient's
parameter may fall in the overlapping region. Thus, in order to obtain a "certain" diagnosis you need to
consider not only the distribution of the parameter(s) but also the patient's values and the extent of the
overlapping region.

Prof can you please elaborate a bit more on the interhuman variability and its difference
with the interpopulation variability please?
Bellelli: every individual is a unique combination of different alleles of the same genes;
this is the source of interindividual variability. Every population is a group of individuals who intermarry and
share the same gene pool (better: allele pool). Every allele in a population has its own frequency. Two
population may differ because of the diffferent frequencies of the same alleles; in some cases one
population may completely lack some alleles. The number and frequencies of alleles of each gene
determine the variance. If you take two populations and calculate the cumulative interindividual variance
of the population the number you obtain is the sum of two contributions: the interindividual variance within each population, plus the interpopulation variance
between the means of the allele frequencies. For example, there are human population in which the frequency of blood group B is close to 0% and other populati
ons in which it is 30% or more.

Prof can you please explain again the graph you have showed us in class about thromboplastin?
(Y axis=abs X axis= time)
Bellelli: the graph that I crudely sketched in class represented the signal
of the instrument (an absorbance spectrophotometer) used to record the turbidity of the
sample (turbidimetry). The plasma is more or less transparent, before coagulation starts.
When calcium and the tissue factor (or collagen) are added. thrombin is activated and begins
digesting fibrinogen to fibrin; then fibrin aggregates. The macroscopic fibrin aggregates cause
the sample to become turbid, which means it scatters the incident light. The instrument reads
this as a decrease of transmitted light (i.re an increase of the apparent absorbance) and the
time profile of the signal presents an initial lag phase, which is called the protrombin or
thromboplastin time depending on the component which was added to start coagulation
(tissue factor or collagen).

Prof can you please explain the concept you have described in class about
the simultaneous hypercoagulation and hemorrhagic syndrome? How can this occur?
Bellelli: The condition you describe is observed only in the Disseminated
Intravascular Coagulation syndrome. Suppose that the patient experiences an episode of
acute pancreatitis: tripsin and chymotripsin are reabsorbed in the blood and proteolytically
activate coagulation causing an extensive consumption of fibrinogen and other coagulation
factors. Tripsin and chymotripsin also damage the vessel walls and may cause internal
hemorrages, but at that point the consumption of fibrinogen may have been so massive that
not enough is left to form the clot where the vessel has been damaged, causing an internal
hemorrage. Pancreatitis is a very severe, potentially lethal condition, and DIC is only one of
the reasons of its severity.

You said that certain drugs (ethanol, cocaine, cannabis, opiates...) cause a
necessity of higher and higher dosage, for two reasons: the enzyme in the liver is inducible and
the receptors in the brain are expressed less and less. So, first, I am not sure I got it right, and
second I did not understand how expressing less receptors leads to a necessity of higher
dosage.
Bellelli: You got it correctly, but the detailed mechanism of resistance may
vary among different substances, and not all drugs cause adaptation.
The reason why reducing the number of receptors may require an increased dosage of the drug
is as follows: suppose that a certain cell has 10,000 receptors for a drug. When bound to its
agonist/effector, each receptor produces an intracellular second messenger. Suppose that in
order for the cell to respond 1,000 receptors must be activated. The concentration of the
effector required is thus the concentration that produces 10% saturation. You can easily
calculate that this concentration is approximately 1/10 of the equilibrium dissociation constant
of the receptor-effector complex (its Kd), the law being
Fraction bound = [X] / ([X]+Kd)
where [X] is the concentration of the free drug.
After repeated administration, the subject becomes adapted to the drug, and his/her cells
express less receptors, say 5,000. The cell response will in any case require that 1,000
receptors are bound to the effector and activated, but this now represents 20% of the total
receptors, instead of 10%. The drug concentration required is now 1/4 of the Kd.
Continuing administration of the drug further reduces the cell receptors, but the absolute
number of activated receptors required to start the response is constant; thus the fewer
receptors on the cell membrane, the higher the fraction of activated receptors required.




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