Mean Value Theorem

•

inhibition of uptake of :.erum

albumin) by leucocytes as an index of inh1.bition of phagocytosis, Chang (1.972) observed that

indomethacin, phenylbutazone and sodl.wn sa]1�­

late suppressed phagocytosis at concentrations approxll:lating to the blood leveli:. achieved ¹ⁿ man with therapeutic doses. A similar observation was made by Di Rosa et al. ('1971). �t thus

appears that suppression of phagocytosis by leucocytes could be invol.ved ^1.n the antl­

infl.umtatory action of these compounds ..

(4) Inhibition of leucocyte mior-ation: :tn ^rats 1.Jnplanted subcutaneously wi.th glass cove.rsllps followed by the inject.ion of ³ H-thym1clirte ^into

the site of implantation. one hour be£ore the coversll.ps we.re removed• D1. Rosa et ^{al... (} 1.971..)

observed tti&t treatment with ant.i-infla, ^im to.cy

drUgs. e.g. indomethacln. salic:yla.t:e.sr etc.

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-d�layed the appearance of thymidine labelled cells adhering to the coverslips. In addi.tion there woo a reductlon in the tot�l number of cells that had emigrated and adhered to the coverslips. In lotcr experiments however, it was obncrved that indomctho­

c�n reversed the inflammatory process at a time when polymorphonuclcar cells hud alraady accumu­

lat�d at the site of inflammolion (Chang, 1972).

It was also reported that aspirin and indomPthac1�

affect only the migration of mononuclear cells and not of polymorphonucleor cells (Van Arman, Carlson, Risley Thomas ^& Nuss, 1970). These

observations argue against inhibition of leucocyte migration as a possible mechanism of action of

anti-inflammatory drugs.

(S) Membrane stabilization: Using inhibition of

-lTheratlon of B-glucuronidase as a measure of

lysosomal Membrane stabilization, lgnarro ^& Collor.ibo (1972) observed that anti-inflammatory ^drugs

stabilize lysosOlllal membranes. However, there

was an inverse correlation between potency as anti.­

lnflar.natory agents and as stabilizers of lysosomal

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-1:1embrane:1. Similor mcmbrnr,c :;tab1liz.1ng cffccta of non-3tcroidol anti-inflcll'.IT\otory agent� woo

reported by r-11 zuahimo, I:shl ^& Mnsumoto ( 1975).

These authors reported thot non-atoroidnl bnti­

lnflam.�atory drugs (3 - tOC uM) inhibited tho

release of ha��oglobin (index of membrDne stabill­

=�tion) when a suspcn:slon of orythrocytou in pho�phate buffer woa heated up to so ⁰ c.

(6) Inhibition of prostaglandin oynth�cic: \'lith the

-demonstration of the presence of prostaglandlns in the infl�Tematory exudate (Willi:s, 1969) and the

cllscovery by Vnne (1971) that non-steroidal anti­

infla:r.t:1atory drugs inhibit prosta9landin synthesis, vane (1971) propo:sed inhibition of prostaglandin

synthesis as a mechanism of action of non-steroidal anti-inflacmatory agents. Inhibition of

prosta-9landin synthesis has been observed in several

syate.�s in vitro. In 1971, Smith ^& Willis obsorved that Platelets fr0111 patients on treatment with

••p1rin could not gene.rate prostaglandind. This effect Ya• found not to be due to inhibition of pho•pholipaso but intorfaronco with proataglandin

ayntho•1•. The rooult hos aince been co1,tinnod by rerroira, Moncada ^& V�nn (1971). The authora

further obccrv1Jd that. in parruocd nple n or th� dog,

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-injection of catecholamines or nerve stimulation

caused a release of prostaglandino which represented fresh synthesis (prostaglandins arc released

repeatedly and in higher concentration than could

be found in the tissue). This release was abolished by indomethacin. In most of the systems so far

studied the rank order of potency of non-steroidal ant1-1nfl.immntory agents against prostaglnndin

synthesis correlates well with the observed anti­

inflanvnatory activity in vivo. ·However, the

potency ratios varied from one enzyme preparation to the other. To explain this Vane (1972) proposed

that the prostaglandin synthetase exists in various molecular forms allowing for varying pharmacolo­

gical profile of action of non-steroidal anti­

inflammatory drugs.

:Inhibition of prostaglandin synthesis as a mechanism of action of non-steroidal anti-inflam­

matory agents appears more attractive than the other mechanis�s of action on the following grounds:

(a) Much lower ^doses of the anti-inflammatory

agents arc required to inhibit prostaglandin

aynthe�is than to uncouple oxidative phosphory­

lation; tor exanple, indomethacin ^{gave a} SO�

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-inhibition cf prostagl�n�in oynth�tnoe octiv1ty at concontr�tion of 0.17 uM 1n 9uinoo-pi9

lung·coll-frco homo90noto cv�no, 1971) whoroas an much ns :?SO uM wao required to pcoduco 50:4 inhibition of oxidl\LJ.vc phonphorylol:ion in

r.i1tochondr1n (Whit•houac ^& Uoolem, 1962).

Th«re was no aign of lyaoaomal mcmbrnno

stnbili:atlon (no chongg in 8-glucuronirtna�

content) at a time whor. ,,�oat..iglrndJ.n r;ynthosia vas inhibited ^by isalicyletcs (\lillia, Davison, •

R�ell, Brocklehurst ^& Smith, ^1972).

(b) The dose of non-steroidal anti-lnflaMll"atory

drugs necessary to inhibit prostaglandin

cynthesis in vitro ls lower than attainable ^• plasma concentration in vivo. It has been

shown that after ^a dose of indomethacin (200 mg

daily) in oan, the free plasma concentration of .lndocethacin C after allowing for 90"

plasma protein binding) 1• approximately 0.2 uq/�l (H1c:lter, Zacchei, Cox, Brodie ^&

cont·o1ell, ¹⁹⁶⁶⁾ which ^WaJI ll!Uch higher than the 1050 value (conccntrot.lon o! the drug

that produce 5� inhibition of PG oynth aia) tor indo«1ethacln ngalnat microaom 1 n�ym•

preparation tron dOg epl on - O.OG ug/ml

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-(Flower, Gryglewski, Herbaczynsta-Cedro ^&

Vane, 1.972). _•

(c) Indomethacin is a potent anti-inflammatory agent, yet the concentration, used to

uncouple oxidative pbosphorylation, or inhibit phagocytosis could not ^be achieved in ·,ivo.

Thus the peak blood level of indomethacin (7.4 ug/ml - Hucker et al. 1966) was only about a quarter of the dose of indOfflethacin used in vitro to inhibit leucocyte phaqocy­

tosis (Chang, 1.972).

In support of inhibition of prostaglandin synthesis as the mechanism of action of non-steroidal anti-inflam­

matory agents is the observation that in arthritic

patients, urinary excretion of prostaglandin metabolites •

was reduced by mor-c than 70% after treatment with aspirin­

like drugs (Hamberg, 1.971.). It has also been shown using the sponge exudate technique (Higgs, Harvey,

Perreira ^& Vane, 1.976) that aspirin-like drugs inhibit pro�taglandin synthesis in vivo •

Anti-lnflcr:u:iatory steroid�

Unlike the non-steroidal anti-inflwnmotory ogento, the ctoroidol onl:1-inflCtMU>Lory agents did not l1ppcor to inhibit proatnglondin oynthoolo in vitro in u�tly

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-inveotigatioas. Vane (1971) observed that steroids, e.g. hydrocortisone failed t,, inhibit pro•toglandin synthesis from orachidonic a•:id by guinea-pig lung homogenate preparation in vl:ro. Ferreira et ol.

(1971} reported that steroids did not a£fect prosta­

glandin release<• synthesis) in response to nerve stimulation or catccholaminc1 in the perfused spleen

of the dog. Prostaglandin release by the spontaneously contracting segments of the rabbit ileum (P���eira,

Herman & Vane, 1972; Lewis & Piper, 1975) was not

reduced by hydrocortisone. In vivo, steroids did not reduce the prostaglandin content of the sponge exudate

(Higgs et al. 19Y6). •

Even though steroids do not appear to inhibit prostaglandin synthesis, there is evidence that they

interfere with prostaglandin metabolism via other mechanis�a.

Ca) Inhibition of phosphollpase A2 activity.

The rate limiting step in the blosynthesls of

prostaglandln ls the cleaosage of the precursors from phosphollpid pools in tha membrane. The enzyme

responsible for this process ls phospholipase A2•

Steroids have been shO'tln to inhibit phospholipase A2

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-activity in the guinea-pig lungs (Flower, 1978) or1d

the rank ordor ot potency wao vary oimil�r to th�ir anti-inflall\/llatory activity.

While this observation may account for tho bono--f icial ebono--fbono--fect obono--f ateroids in allergic asthma, it ia

doubtful if this could be the mechaniam of anti­

inflar.-.matory action of stcroido since thoy do not

reduce prostaglandin generation in vivo (Higgs, et al.

1976). Perhaps the rate of release of the precurooro could explain the difference. In aDthma, the release of the mediator la �uantal in nature �h1le prostaglondin

levels in influr.iation gradually build up over a period of t ^ii=e.

(b) Inhibition o! Release

In perfused epigaatric tat • ^pad of rabbits, l1polys1� induced by close-arterial infusion of

adreno-<:orticotrophic horr.ionc ^(ACTH) woa accompanied by PG£2 �o:nation in the tot tinz.uc end dilatation

er. the blOOd vcccela giving an incrc o d ^blood flow

(Lcvici t. J>i�c , ^1975). Infucion of hydrocortiaonc

�fa,:c activating U,o fat pad with ACTII gr otly r ^{_;r- �} ar abo1S h d Ute vaoodllatotion WhlJ

evSt 9 ,,, r�t _t ^OJ• _�t.:2 ^t nt nt of tho tnt. r I.

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-Thus hydrocorti:ionc did not i11hibit PG synthesis

during lypolysis (Lewis ^& Pipor, 1975). The action of hydrocortisone was due neit.her to a direct anta­ •

gonism of PG action (since fur,ctional vasodilatation accompanying PGE2-ind�ced lipulysis was not inhibited by hydrocortisone) nor due to inhibition or lipolysis itself since the same level ot free fatty ncid was

attained in the absence and also in the presen�c of hydrocortisone. But when the venous effluent from

•

the fat pad was superfused over a series of isolated smooth muscles to detect prostaglandins, the authors observed that activation with ACTH caused the release

of PG-like activity and this was reduced when hydro- _• cortisone was infused into the fat depot. It was

possible then that hydrocortisone prevented the

releftse of PG-like activity into the venous effluent.

This was confirmed in a study in which act\lal prosta­

glandin content of both fat tissue and supernatant was measured in the absence and in the presence of

hydrocortisone (Chang, Lewis ^& Piper, 1976). :tn this study, it was observed that in the activated fat pad of the rabbit, there waa a greater amount of prostaglandin in the tissue when extracted than

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-was found in the supernatant after the system had

been incubated with hydrocortisonc. On the contrary, incubation with indomcthacin (non-steroid) reduced

the prostaglundin content of both tissue nnd super­

natant to below basal level. Since indomethacin is known to inhibit prostaglandin synthesis (Vane, 1971), Chang et al. (1976) inferred that steroidal anti­

inflammutory agents inhibit proat4glandin release and not its synthesis. According to Lowis ^&

Piper (1975) steroids are not likely to be effective in situations where prostaglandin formation occurs

extracellularly or in necrotic tissues where the cells are damaged so much that their membranes no

longer provide a barrier to the diffusion of materials.

In the activated cpiga�tric fat pad of the rabbit, lipolysis is not accompanied by damage to the fat cells. Under this condition, release of prosta­

glandins from the fat cells represents an active transport process rather than leakage (cf. Blto,

1972; Bito, Wallenstein ^& Baroody, 1976). This active transport process is affected by steroid.

In view of this suggestion, the results of the

experi�ents with sponge exudates (Higgs et al. 1976)

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-- ³⁷

-should be interpreted with c a ution. It i� ponsible th�t lcucocytes which accumulate in the cY.udotc

rct�in some prostoglondin which ere not releoQed 1nto the exudate. Prontaglandino ore mCJnbrone substances which are easily released by the slightest mcchonicol

injury including touch. Thus, �quoo&ing of the cpongcs while tryping to drain them of the exudate might lead to the leucocytes releasing the retained prosta­

glandins. Under that condition, a compound that is _• supposed to prevent the release of prostaglandin

would appear inef:ective.

Cc) Inhibition of PG synthesis

Some recent �xperiments show that steroidal anti-infla.r:imatory drugs do inhibit PC synthesis.

Taahjion, Voelkel ^& McDonough (�975) observed that hydrocortisone in very low concentrations inhibited prostaglandin synthesis by mouse fibrosnrcoma cells in vitro. This group of workers failed to record any increaae in proatnglandin content of the fibro­

sarcoma cella implying that thero was no inhibition of PG relceac. Similarly, Kontrowit:, Robinson,

McGuire ^& Lovino (�975) roporled that doxnffi�lhaaone inhibited proataglandin production by rheumatoid

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-synovia. These later experiments would tend to complement·the earlier observation of Greaves ^&

t,\cDonald-Gibson ( 1972) that some steroids inhibit prostaglondin synthesis in human skin homogena te.

It therefore seems that whether or not a steroid would be effective in inhibiting prostnglandin

synthesis is a function of the sensitivity of the enzyme preparation to the particular steroid since

enzyme systems from different sources respond

differently to different {or even the same) anti­

inflammatory drugs (Vane, 1972).

-Other anti-1nfl,mmatory agents.

Some anti-inflanvnatory drugs seem to produce thei� effects independently of the prostaglandin system. Colchiclne (Higgs et al. 1976; Glatt,

Wagner ^& Brune, 1976) the anti-gout drug and some ne�er non-steroidal anti-inflammatory drugs such as eenoxaprofen (Cashin, Dawson ^& Kitchen, 1977) and Abbot - 29590 (Carter, Dodge, Krause, Young, Swett,

'1974) showed potent anU-inflanvnatory activity in the rat hind paw oedema but had no effect on pr-osta-glandin synthesis in vitro. Other drugs such as

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-Phenclzine, Chlorpromazine and deGipr�mine (Lee, 1974) can inhibit prostaglandin synthesis in vitro but lack

anti-1nflammalory activity in vivo. It does seem therefore that prostaglancUn tynthetase inhibition

1s a common charactcrictic of many non-st�roidol

anti-infl.immatory agents but is not always correlated or ossociated with anti-inflarimo.tory potency or

activity. However, among the non-stc.roidal anti­

inflammatory drugs now in use, there is a good

correlation between anti-inflammatory acti'li ty and ant1-prostagland1.n synthetase activity.

'l.3.3 Ccllul�r exudation in inflammation: Role of Prostaol�ndlns

The characteristic sequence of cellular events in inflammatory response is the early accumulation

of polymorphonuclear cells (PMtls) at the site of

1-nflanunation and the late accUlllulation of mononuclear cells (Spector ^& Willoughby, '1963); Rebuch ^& Cowley, '1956). In chronic 1nflainmat.t.on, few PMtJs arc seen and

the predomJ.nant cells are small and large mononuclear cells including monocytes, larger granular monoclear

phagocytic cells (macrophages), multi-nucleated ^• giant cells and cells of the lympoid series •

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-The timing of the change from PMNs to mononuclear

cell predaninance depends on the nnture of the inflammatory stimulsu. For example, in calcium pyrophosphate as well

as carragenin-induced inflammation in the rat, PMNs

dominate both the early and the late phase of the inflor:,­

mntory reaction (Willoughby and Dieppe, 1976). ln these two cases, however, there is n detectable increase in

the number of mononuclear cells in the late phase of the inflaramotory reaction but PMNs still dominate the

exudate. However, in Arthurs reaction and cell mediated immune reactions, transition from PMNs to mononuclear cells can be detected as early as eight hours after the stimulus (Willoughby ^& Dieppe, 1976). Later mononuclear

cell predominance in inflammation might be due to ^diffe­

rent chemotactic stimuli for the cell types as cell migration in pleural exudate appears to be sequential

(Hurley, Ryon � Friedman, 1976). lt may also be due to different survival rates (Paz ^& Spector, 1962; Marchesi,

1964) of the cells.

PGt:1 is leucotactic (Kaley ^& iteiner, 197'1; Mccall

£ Youltcn, '1973). It is possible that prostaglandin formation at t,e site of inflamt:totion �ay precede the

e�i9rntion o! lcucocytes. Proataglondino nre rclooacd fror:i pol"jCiorphonuclocr l�ucocytcs during phngocytosis

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-(H1g�• � Youlten, 1972) �h1ch attract more l�ucocytoa.

The interpla)' between ^lhe loucocytca and proal11glond1n•

probably conatilute a 8yalc:m which ma1nta1na the infl��tor\' atate.

Ttle-re hove been a "' rnl hypolhcoeo J.mpl1c:nt1ng pharoacologic�lly ac:llvo cubntancca 1n the ccgulotlon

of body tc:,.pcr.aturc. ^One propcoltion ^ia that ^bod

¹

¹

��ra�-ure in oa ale 1a regulate� by o balanced r"'Clcase of no Snc,ii (S-KT and 1:oradr11nollne) .and

acct:� lc:J'\gl1n1!! at ^hypoth lamic site:. <.Feldbccg ^& r1yera, 1� �; Loaax. �970; t:yers, 1971; Bligh, Cottle ^& Ma:.kroy,

�9��,. The fir�t �jor evidence 1Qpl1cating proo�a­

�lcndlr.s ^(F-G: 1n pyrcxJ.a va£ ccpcrtcd 1n 1970 when

& t:!"..dlar.t cb:ervcd pronlaglandin-likc subotancc

�n cerc.t:_--o:.?inal ^fluid collected fr01D a febrile cat.

r;-r:s..er��e� 1n favo:::r of a role for proatoglandin in

- ^•

•

lar...,1r ^of t.ho ^E: and r a r1 ore no -��to ^c;t y� thol le tlaauo <t 1 ea ^&

' e>.

l ^{1 al In)}

l

1

. �

C t l

t r ^t

-•

l

I

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-1971b; Feldberg ^& Saxena, 1971a; Potts ^& East, 1972; Nistico ^& Marley, 1973; Lipton ^& F?ssler,

1974). Unlike the monoamines which produce

hyperthermio in some species and hypothermia in others (f'eldberg ^& 1-lyers, 1964), PGs ai:-e hyper­

thermic in all species studied (Pcldberg ^& Saxena, 1971).

(3) Arachidonic acid causes a rise in body temperature when injected into the cerebral ventricles (Girault

et al. 1973; Splawinski et al. 1974 both quoted by Coceani ^& Pace-Asciak, 1976) which was delayed in onset. The effect is abolished by antipyretic

dn.igs confirming th� presence of prostaglundin synthetase in hypothalamic tissue and that the fatty acid acquired pyretic activity upon conver-sion to a prostaglandin.

(4) The anterior hypothalamic pre-optic area is the tdrgct of PG action (Peldberg � Saxena, 1971.b;

Stitt, 1973; Veale r. Cooper, 1975). Pyrogens act most intensely at thot site (Cooper et al.

1967; Veale ^& Coopea·, 1975; Myers et nl. 1974).

The c��c region ls probably involved with the

ontipyrctic effect of drugs (Crt,nston e. Rawlins,

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.. .- - ·- - --- - - - =-- - - - ---:===,-:;- =-=--= -=-- -

-- ⁴³

-1972; Avery ^& Penn, 1974).

(S} The magnitude and time course of PGE and pyrogen fever ore identical (Stitt, 1973; Bligh ^& Milton,

1973; Veale ^& Cooper, 1975).

(6) Pyrogen fever is associated with the appearance of, or increase in prostaglandin activity in the cere­

brospinal fluid.

Prostaglandin levels parallel the course of the febrile episode and antipyretic drug treabTlent is effective in

reducing both fever and prostoglandin synthesis (Peldbcrg

& Gupta, 1973; Peldbcrg, Gupta, 11ilton ^& Wcndlant, 1973;

Dey, Feldbcrg ^& Wcndlant, 1974a).

Xt 1s possible then that prostaglandins endogenous to the anterior hypothalamus mediate the fever responses to pyrogen. tn vever, heat production and heat loss remain unchanged but the hypothalamic thermostat is set higher than norr.,al. The fact that antipyrctlc substances do

not lower normal body temperature and where seme of them do lower non'lal body te�perature, the action docs not

involve prostaglandlns (Milton, 1973), has given rise to the idea that prostaglandin may not be important in the regulation of norMal body temperature but bccocnc impor-tant in a nituation where the ^body tc�perature in high.

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-Prostaglandin 1.n Analgesia

It has not been easy to assess the role 9f prosta­

glandins in the mediation of pain. However, the firat indication that prostaglandins might be involved in

the production of pain was reported by Bergstrom,

Ouner, von Euler, Pernow & Sjovoll in 1959 when they observed that in man, intravenous injection of prosta­

glandins caused headache and pain along the veinc into which they were infused. There is also evidence which

auggests that prostaglandins or an intermediate in their biosynthcsis mediate the pain producing activity of

bradykinin (Piper & Vane, 1969, Collier & Schneider, '1972}.

(a} Both _PG&1 and bradykinin injected intraperitoneally induce • a writhing (pain) reoponsc in mice. The

pain producing action o! bradykinin hac o lalent period while that of PGE 1 is immediate.

(b) Aspirln-:ike drugs inhibit the action of bradykinin but not chat of _PG&1•

It io poi;<Jiblc that prostaglandino may not be the pricary mcaJ.a,.or:. of poin but may enhance the effect of _• other nociccpl.1vc subatnnc�s, f'errciro (1972) observed _•

thot separate oubdcrmnl infusion of _PGc1, brodyk1n1n, ,1�tnmino or ^II mlxturP. of brodykinin ond hiotominc did

'\Ot prcduco o•·ert pain in man but ^"'hen l'G&1 woo uddctl

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-to either bradykinin or histaraine, a strong pain react�on occurred. FerreJ.ra (1972) therefo�e concluded th�t

continuous generation of cdnuto araounts of prosta;landin at a site of injury 5en&itizes the nerve endings ^!O

that mechanical stimulation or release of mediators such as bradykinin or histamine can cause pain.

Ob1cct1vc of tho Present study

DBA is related :>tructurally to acctylsalicylJ.c: acid (Fig. 9) which i:s an e:stablished analge:,ic, ant.ipyrcU.c and ant.1.-.inflamr.iatory substance.

For many years aspirin has been used in the treatment of slc:klo coll cri:,is for its onalgeaico ond pr-obnbly

its antiprothrombin effects. The finding by Ekong at al. (1975)"that ODA which bearo some structural rc�em­

blancc to aoplrin po�oesoed onti-oicklin; activity in vitro, prompted this invesllgolion into the onci-inflMl­

i:,atory and related phnnnacologicol properties of ^l)BA.

Fogoram1da (Pipcronyl-4-ocryliclsobutylrunidc) is another oct1vc principle which hoe bcon oxtroctcd from

the root bnc� of ragoro (Cnyonlhi, 1975). Thin co.�pound hoa boeo Jncludod in thio otudy for two main rcaoons:

(1) The crude extract of Pagorn hno bean chown to poz.oeua cnt1-ciclcl1ng of:f'1:ct (Sofoworn ^& lac nco,

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In document Calculus One (Page 174-179)