A brief description on the importance of host modulation therapy in periodontology.

1. HOST MODULATION
THERAPY
SAHLA AMBADI
PG- II

2. CONTENT
• INTRODUCTION
• DEFINITIONS
• HISTORY
• PATHOGENESIS OF PERIODONTITIS AND THE HOST
RESPONSE

3. CONTENT
• AGENTS USED IN HOST MODULATION
• - NSAIDS
• - ANTI- PROTEINASE BLOCKING OF MMPS
• - BISPHOSPHONATES
• - ANTI CYTOKINE THERAPY
• - AGENTS CAUSING DISRUPTION OF CELL SIGNALING PATHWAYS
• - COMBINATIONS
• CONCLUSION
• REFERENCE

4. INTRODUCTION
• Periodontitis is a complex infection initiated by bacteria –tissue destruction.
• In the past, the understanding of the etiology and the pathogenesis of the periodontal disease focused
on the microbial aspect of the diseases -- therapeutic efforts focused on the mechanical removal.
• Recently, --recognized -- host response to bacterial infection which causes greater destruction of the
connective tissue elements, periodontal ligament and alveolar bone -- therapeutic efforts focus on
altering (modulating) the host response -- various host modulating approaches.

5. DEFINITIONS
Host: the organism from which a parasite
obtains its nourishment/ an individual who
receives a graft.
Modulation: the alteration of function or
status of something in response to a stimulus or
an altered physical or chemical environment.

6. HOST MODULATION THERAPY (HMT) -
Treatment concept that aims to reduce the tissue destruction
and stabilize or even regenerate the periodontium by modifying
or down regulating destructive aspects of the host response and
up regulating protective or regenerative responses.

7. RATIONALE
• offer the oppurtunity for modulating or reducing destruction by treating chronic inflammatory
response.
• Used as an adjuncts to conventional PD treatments (SRP & Surgery)
• HMTs do not “switch off” normal defense mechanisms or inflammation; instead they
ameliorate excessive or pathologically elevated inflammatory processes to enhance the wound
healing and periodontal stability.

8. HISTORY
• (1973) Socransky, -- sites of advanced bone loss harbored an anaerobic microaerophilic Gram-
negative flora that was totally different from the primarily facultative Gram-positive organisms
found at adjacent healthy sites.
• Klein and Raisz -- prostaglandins -- potent stimulators of bone resorption in tissue culture.
• Paul Goldhaber and Max Goodson (1970) -- arachidonic acid metabolites as important
inflammatory mediators of the bone loss in periodontitis.

9. • Concept of Host Modulation - William and Golub (1990)
• Various agents modulate specific component of disease pathogenesis which includes regulation
of arachidonic acid metabolites, excessive production of matrix metalloproteinases (MMPs),
immune and inflammatory responses and bone metabolism.

10. PATHOGENESIS OF PERIODONTITIS
• Linear Bacterial Model
• Circa Model
• Non linear Model
• Linear Bacterial Model (1990): depicting bacteria to have a principal etiologic role in the
initiation and progression of periodontal disease.-(Haffajee and Socransky 1990)
Microbial
challenge
Clinical signs of
disease initiation
and progression

11. PATHOGENESIS
Circa Model
-- central role for the host immuno- inflammatory response.
Microbial
challenge
Clinical signs
of disease
initiation and
progression
host immuno-
inflammatory
response

12. Non linear model

13. Periodontal Balance

14. AGENTS FOR HMT
NSAIDS
Anti proteinases
Bisphosphonates
Anti cytokines
Combinations
Otherss

15. NSAIDS
• NSAIDs inhibit the formation of prostaglandins, including prostaglandin E2 (PGE2) (Grenier et al 2002).
– Produced in response to lipopolysaccaride(LPS)-
• Upregulates bone resorption by osteoclasts;(Heasman PA and Collins JP1993)
• Levels of PGE2 are elevated in pts with periodontitis ( Plamondon and sorsa jp 2002)
• Inhibits fibroblasts function and has inhibitory effects on the immune response (Grossi and Genco Ann
Periodontics 1997).

16. • Studies have shown that systemic flurbiprofen, indomethacin, naproxen,
administered daily for periods of up to 3 years, significantly slowed the rate of
alveolar bone loss.

17. • Vane(1971) -- aspirin and aspirin-like drugs inhibited the production of prostaglandins by
inhibiting the COX enzyme.
• Goldhaber et al. (1973) added indomethacin, a known inhibitor of COX, to the culture media,
observing a decrease in bone resorption of up to 50%.
• Nyman et al (1979)… animal study… systemic doses of indomethacin… delayed the onset
and suppressed the magnitude of the acute inflammatory response and decreased the amount
of alveolar bone resorption.

19. Side Effects of NSAIDs
• Daily administration for extended periods of time (years rather than months) is
necessary for periodontal benefits to become apparent.
• Hemorrhage due to anti platelet activity.
• Gastric ulceration.
• Renal failure.
• Rebound effect.
• Liver failure.

20. Anti- Proteinase Action on MMPs
• Matrix metalloproteinases (MMPs) are a large family of zinc and calcium-dependent
endopeptidases, which are responsible for the tissue remodeling and degradation of the
extracellular matrix (ECM), including collagens, elastins, gelatin, matrix glycoproteins, and
proteoglycan. (Woessner ,1991)
• MMPs are inducible enzymes, upreguated by pro inflammatory cytokines (especially IL-1, TNF-
α, PDGF, FGF have all been shown to increase production of MMPs).

21. • Primary source of MMPs in the gingiva was found to be the neutrophil (Golub et al 1992)
• Levels of collagenase activity correlate with disease activity (Ryan et al 1998)
• Imbalance between activated MMPs and their host derived endogenous inhibitors, lead to
break down of ECM during periodontitis (Birkadel-Hansen H 2003)

22. • Matrix metalloproteinases play key roles in the degradation of the extracellular matrix,
basement membrane as well as in the modification of cytokine action and activation of
osteoclasts.
• The expression and activity of MMPs in non- inflamed periodontium is low but is
drastically enhanced in the inflammatory conditions.

23. Inhibition of the activity of MMPs:
• TIMPs
• α2 Macroglobulin
Endogenous
• CMT (Chemically modified
tetracycline)
• SDD
Exogenous

24. Endogenous inhibitors of MMP-- fibroblasts, keratinocytes, monocytes/ macrophages, and endothelial
cells.
• Four TIMPs (TIMP 1–4) are known: TIMP-1 ,TIMP-2 , TIMP-3 and TIMP-4.
• TIMPs appear to regulate matrix degradation both by proteinase inhibition and by blockage of
autolytic MMP activation. (DeClerck,1991).
• Other functions-cell differentiation, growth and migration, tumour growth inhibition.
Tissue Inhibitory Metallo Proteinases (TIMP)

25. • The first TIMP -- 1975 as a protein, in culture medium of human fibroblasts and in human
serum, which was able to inhibit collagenase activity.
• TIMP-2 regulates the activation of pro-MMP-2 by binding to its c-terminal region.( Ward et al,
1991)
• TIMP-3 Prevents the activation of pro MMP -2 by MT1-MMP.
• It has an affinity for components of the ECM.
• TIMP-4- MMP-14, MMP-2.

26. • Protein present in blood- - antiprotease.
• synthesized -- in liver, macrophages, fibroblasts, and adrenocortical cells.
• It functions as an inhibitor of MMPs(2, 9).– form complexes.
• Inhibitor of blood coagulation.
• Carrier protein -- binds to numerous growth factors and cytokines, such as platelet-derived
growth factor, basic fibroblast growth factor, TGF-β, insulin, and IL-1β.
Alpha-2 Macroglobulins (α 2 M)

27. TETRACYCLINE
Capability of inhibiting the activities of neutrophils, osteoclasts, and matrix metalloproteinases
(specifically MMP-8), thereby working as an anti-inflammatory agent that inhibits bone destruction.
Prevent CT breakdown via-
1. Mediated by extracellular mechanisms
2. Mediated by cellular regulation
3. Mediated by pro anabolic effects
Golub in 1983 administered minocycline and fall in collagenase level was noted.
Entire tetracycline group of family exhibit anti collagenase effect.

28. Mediated by extracellular mechanisms
• Direct inhibition of active MMPs.
• Inhibition of oxidative activation of pro-MMPs.
• By promoting excessive proteolysis of pro-MMPs
into enzymatically-inactive fragments.
• Inhibition of MMPs protects α1-proteinase
inhibitor, thus indirectly decrease serine proteinase
(elastase) activity.
2. Mediated by
cellular regulation
• decrease
cytokines,
inducible nitric
oxide synthase,
phospholipase A2,
prostaglandin
synthase.
Mediated by pro-
anabolic effects
• increase
collagen
production,
osteoblast
activity and
bone
formation.

29. • Golub et al. (1987) -- antimicrobial and anti collagenase properties of tetracyclines resided in
different parts of four ringed structures.
• Carbon -4 position side chain was responsible for the antimicrobial activity of tetracyclines --
altered the structure of tetracyclines -- development of CMTs.
• They were produced by removing the dimethylamino group from the carbon-4 position of the A
ring of the four ringed (A,B,C,D) structure.
CHEMICALLY MODIFIED TETRACYCLINE (CMT)

31. • The resulting compound, 4- de dimethyl amino tetracycline (CMT-1) did not have
antimicrobial property but the anticollagenase activity was retained both in vitro and in vivo.
• Further modifications in the central structure of tetracyclines by addition or deletion of
functional groups resulted in the formation of eight CMTs.
• Ca and Zn binding sites at the carbonyl oxygen and the hydroxyl groups of carbon-11 and
carbon-12 positions are responsible for the anti-collagenase action of the CMTs.

33. • inhibition of mammalian collagenase,
• inhibition of neutrophil chemotaxis;
• Increased fibroblast attachment to the root
surface.
• anti-inflammatory effects due to the
inhibition of prostaglandin synthesis (high
doses)
• inhibition of bone resorption and
enhancement of collagen synthesis
The non-anti-
microbial CMTs-

34. CMT 3 -most potent
collagenolytic CMT
(Rifkin et al 1994) CMT 1,3,6,7 & 8 : effective
inhibitors of bone
resorption.
CMT 2 &4: block PMN
collagenase

35. • Photosensitising property
• Neurotoxicity
• Cytotoxic effects at higher concentrations
Adverse Effects

36. Minocycline, doxycycline and tetracycline
were all shown to inhibit collagenolytic
activity(Golub et al. 1984).
Ramamurthy & Golub et al 1983
diabetic mice
orally administered Minocycline
abnormally elevated anti-collagenase
activity in gingival tissues compared to
controls

37. DOXYCYCLINE
• Most potent anticollagenase activity
• Much lower IC 15 μm than minocycline (190) or tetracycline(350).
• More active against PMN type collagenase(MMP-8) than fibroblast type. (Golub and Smith 1995).
• Rationale for using SDD as HMT – doxycycline down-regulate activity of MMP’s by variety of
synergistic mechanisms

38. • Doxycycline tends to be highly concentrated in GCF at levels 5-10 times greater than serum and
show substantivity as they bind to the tooth structure & are slowly released as still active agents
(Pascale et al 1986)
• The first clinical study prescribing SDD as an adjunct to mechanical debridement showed
statistically significant reductions in GCF concentrations of MMP-8 and MMP-13 compared with
placebo. (Golub et al. 1997)

39. Inhibition of production of epithelial derived MMPs.
•Direct inhibition of active MMPs by cation chelation.
•Inhibition of oxidative activation of MMPs.
•Down regulation of pro inflammatory cytokines
(IL-1,IL-6, PGE2, TNF)
•Scavenges and inhibits the production of ROS.
•Stimulates fibroblast collagen production.
•Reduces osteoclast activity and bone resorption.
•Blocks osteoclast MMPs.
•Stimulates osteoblast activity and bone formation.

40. DEVELOPMENT OF SDD
• Long term administration of 50-100mg of Doxycycline for 2-7yrs in refractory periodontitis -
resistant sub gingival flora as adverse actions (Kornman and Karl 1982).
• Therefore development of SDD of 20mg which had anticollagenase property with elimination of
antimicrobial property. (Golub et al 1990)
• Studies -- low dosing of 20mg over 3mths could successfully prevent the progression of
periodontitis without the emergence of resistant microbes and without any adverse effects.

41. AUTHOR DURATION STUDY GROUPS SUBJECTS
Preshaw et al
(2003)
9 months SRP+SDD (SMOKERS)
SRP+SDD(NONSMOKER)
SRP+PLACEBO(SMOKERS)
RP+PLACEBO(NONSMOKERS)
41
66
26
76
Preshaw et al
(2005)
9 months SRP+SDD (SMOKERS)
SRP+SDD(NONSMOKER)
SRP+PLACEBO(SMOKERS)
RP+PLACEBO(NONSMOKERS)
81
116
60
135
Needleman et al
(2007)
6 months SRP+SDD(ALL SMOKERS)
SRP+PLACEBO(ALL SMOKERS)
18
16

42. • SDD is approved by US FDA, UK Medicines & Healthcare Products Regulatory Agency
• PERIOSTAT
• (CollaGenex Pharmaceuticals Inc. Newtown PA)

43. Indications
Motivated
patients
Chronic and
aggressive
periodontitis
patients
treatedtreated
non surgically.
(Caton J et al,
2000,Preshaw et al
2005)
Patients
traditionally
considered
resistant to
periodontal
treatment
(smokers).
Cases
considered
refractory to
treatment and
those with risk
factors like
diabetes and
smoking.
Patients with
the periodontitis
associated
genotype (PAG)
have specific
variations in the
gene that
regulates IL-1.

44. History of
allergy or
hypersensitivity
Pregnant and
lactating
women or
children less
than 12 yrs of
age
conditions like
gingivitis and
periodontal
abscess or when
an antibiotic
regimen is
necessary.
May reduce the
effectiveness of
oral
contraceptives
Contraindications:

45. BISPHOSPHONATES
PYROPHOSPHATES BISPHOSPHONATES
• Affinity to bind to hydroxyapatite crystals and prevent their growth and dissolution.
• Increase osteoblast differentiation and inhibit osteoclast recruitment and activity.
• Widely used in the management of systemic metabolic bone disorders such as tumour-induced
hypercalcaemia, osteoporosis and Paget’s disease (Fleisch 1997).

46. Non-Nitrogenous Compounds
•Etidronate (Didronel) Clodronate (Bonefos,
Loron)
•Tiludronate (Skelid)
•metabolised by oseoclasts, & initiates apoptosis
in them, leading to an overall decrease in the
breakdown of bone.
Nitrogenous-Pamidronate
•Neridronate
•Alendronate (Fosamax)
•Risedronate (Actonel)
•Zoledronate (Zometa, Aclasta)
•bind and block the enzyme essential for
connecting some small proteins to the cell
membrane which affect both osteoclastogenesis,
cell survival, and cytoskeletal dynamics.

47. TISSUE LEVEL CELLULAR LEVEL
↓ bone turnover due to ↓ bone resorption ↓ osteoclast recruitment
↓ number of new bone multicelllular units ↑ osteoclast apoptosis
Net positive whole body bone balance ↓ depth of resorption site
↓ release of cytokines by macrophages
↑ osteoblast differentiation and number

48. Various mechanism of action
Inhibits the development of osteoclasts
Induce osteoclast apoptosis (Huges DE Wright KR)
Reduce osteoclast activity (Sato M,Grasser W)
Prevent osteoclast development from haematopoeitic precursor (Huges DE,Mac Donald BR)
Alondronate increases the intracellular calcium content in osteoclast cell lineage ( Colucci S,Zambonian )
Down regulate bone resorption by inhibiting MMPs (Teronen O,Heikkila P)
Stimulates production of osteoclast inhibitory factor (Vitte C,Fleisch H)

49. Long-term use may suppress bone turnover
and compromise healing of even physiologic
micro-injuries within bone (Odvina et al 2005)
Clinically, is essentially exposed bone in the
maxilla or mandible that does not heal within
8 weeks of identification (Wang HL et al
2007)
Patients with previous dental problems -
higher risk of osteonecrosis of the jaw.(William
Giannobile (2008)
Drawbacks:

50. ANTI-CYTOKINE THERAPY
• Cytokines -- regulatory proteins controlling the survival, growth, differentiation and functions of
cells.
• Produced transiently at generally low concentrations, act and are degraded in a local
environment.
• Cytokine-producing cells are often physically located immediately adjacent to the responding
cells.
• Increased expression of IL-1 and TNF in inflamed gingival and high levels in the GCF of
periodontitis patients, several studies -- increased production of these cytokines may play an
important role in periodontal tissue destruction.

51. Anti- cytokine therapy –aimed at-
• Antagonising pro-inflammatory cytokines
• Disrupting cell signaling pathways
• Recombinant anti inflammatory cytokines

52. Cytokine receptor antagonists
Soluble cytokine receptors
Anti-cytokine antibodies
Downregulation -of cytokines

53. Antagonising pro-inflammatory cytokines:
Cytokine receptor antagonists –
Bind to the receptor present on the target
cell and prevent the cytokine from binding
to the target cell. -- no activation of the
target cell.
Example: IL-1 receptor antagonist,
anakinra
Soluble cytokine receptors
Downregulation – by binding to the cytokine
in solution and prevent signaling.
Transactivation - binding the cytokine and
blocks on otherwise non-responsive cells.
Anti-cytokine antibodies
Antagonist in function and decrease the
levels of cytokines. (Anti IL-6 Ab, Anti
TNF- Ab)
Eg. infliximab

54. Author
Assuma et al.
(1998)
Effects of soluble receptors to IL-1 and
TNF during ligature-induced
experimental periodontitis
IL-1,
TNF
inhibited the recruitment of
inflammatory cells in close
proximity to bone, the formation of
osteoclasts and the amount of bone
loss.
Graves et al.
(1998)
Effects of soluble receptors to IL-1 and
TNF during ligature-induced
experimental periodontitis
IL-1,
TNF
inhibited osteoclast formation and
progression of inflammatory cell
infiltration towards alveolar bone
Martuscelli et
al. (2000)
Effects of subcutaneous injection of
rhIL-11 during ligature-induced
Experimental periodontitis
IL-11 Statistically significant differences
in CAL and
radiographic parameters
Delima et al.
(2001)
Effects of soluble receptors to IL-1
and TNF during ligature-induced
experimental periodontitis
IL-1,
TNF
loss of connective tissue attachment
and the loss of alveolar bone height
Oates et al.
(2002)
Effects of soluble receptors to IL-1
and TNF during ligature-induced
experimental periodontitis
IL-1,
TNF
Radiographic bone loss was reduced
by 50% in the experimental group
compared with the placebo group.

55. 1. Infliximab (Remicade)
(Monoclonal Ab to TNF-α)
•Anti-TNF-α antibodies has
effectively attenuated or
prevented inflammation of
arthritis in experiment models.
2. Etanercept (Enbrel)
(soluble form of TNF
receptor)
•TNF-α can also be neutralized
with genetically engineered
TNF-α-RII.
•Etanercept (enbrel) is a fusion
protein. It has been
successfully used in some
autoimmune diseases:
3. Anakinra (Kineret) (rIL-
1RA)
• It competitively inhibits the
binding of IL-1 to the
Interleukin-1 type receptor.
• Anakinra blocks the
biological activity of
naturally occurring IL-1,
including inflammation and
cartilage degradation
Commercially Available Preparations

56. Down regulation of the immune
system. In rhematoid arthritis
therapy with infliximab, cases of
opportunistic infections have been
reported. (Keane et al. 2001)
Importance of screening
patients with diseases like TB
is necessary before such a
therapy.
The harsh enzymatic environment in
periodontal lesions may necessitate
more frequent administration of the
active agents to the defects.
Important cellular functions are
usually backed up in mechanisms
where one cytokine can compensate
for the loss of another.
Drawbacks

57. Disruption of Cell Signalling Pathway
Signal transducers closely involved in inflammation are-
• Therapeutic strategies have been directed towards many of these major signaling pathways,
notably MAPK and NF-κB
• NF-κB(nuclear factor kappa B cell)
• PI3 (phosphatidylinositol-3 protein kinase )
• JAK-STAT (janus kinase-signal transducer
and activator of transcription)
• MAPK(mitogen activated protein kinase)

58. NF-κB
• A protein complex found in the cytoplasm of most human cells, that controls the transcription of
DNA.
• Involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet
irradiation, oxidized LDL, and bacterial or viral antigens.
• key role in regulating the immune response to infection.
• Incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases,
septic shock, viral infection, and improper immune development.

59. • In vitro studies have established that both P. gingivalis and other periopathogenic bacteria
can activate NF-κB in periodontal tissues (Sugita et al 1998)
• An increased expression of NF-κB (p50/p65) at sites of periodontal inflammation
compared with healthy sites in human periodontitis (Ambili et al 2005)

60. MAPK pathway
• ERK1/2 (activated by growth factors)
• JNKs
• p38.
All three MAPK families are assumed to be expressed in diseased periodontal tissues,
although the level of expression may differ depending upon the exact cell types
activated and the degree of inflammation.
(activated by proinflammatory cytokines
and cell stress inducing factors)

61. MAPK
• Induces synthesis of pro-inflammatory cytokines, such as TNF, IL-1, IL-6, IL-8 and controls the
synthesis of other compounds, including chemokines, MMPs and PGs.
• Several imidazole compounds capable of inhibiting it. These are cytokine-suppressive anti-
inflammatory drugs (CSAIDs) responsible for in vitro and in vivo inhibition of lipopolysaccharide-
induced TNF-α expression.
• CSAIDs were initially shown to inhibit various inflammatory cytokines before the p38 MAPK was
actually discovered. Thus, this class of agents defined the role of p38 well before the activation,
regulation and substrates of p38 MAPK were identified.

62. IL-11 has been shown to inhibit the production of IL-1β , TNF-α,IL-12 and nitric oxide (NO) in a
variety of inflammatory conditions.
Martuscelli et al. (2000,2006) investigated the ability of recombinant IL-11 (rhIL-11) to reduce
periodontal disease progression in dogs with ligature induced periodontitis, significant reduction in
the rate of clinical attachment and radiographic bone loss were observed after an 8- week period of
rhIL-11 administration, twice a week.
Recombinant anti inflammatory cytokines

63. Combinations
• Subantimicrobial dose doxycycline (20 mg twice daily), flurbiprofen (50 mg four times per day),
or a combination of the two drugs, for 3 weeks.
• Gingival biopsies were obtained from the planned surgery sites before and after drug therapy.
• Three weeks of SDD alone-- significant reduction in host-derived neutral proteinases,
- flurbiprofen alone -- no reduction.
• The combination therapy -- statistically significant synergistic reduction of collagenase, gelatinase
and serpinolytic activities and a lesser reduction of elastase activity. Lee HM et al.(2004)

64. • A similar effect -- when chemically modified tetracyclines are administered together with
flurbiprofen in arthritic rats. (Leung M et al. 1995)
• CMT-8, has been combined with a Bisphosphonate (clodronate) in rats with experimental
periodontitis. (Llavaneras A et al. 2001)
• Subantimicrobial dose doxycycline has also been combined with the locally delivered doxycycline
gel (10%; Atridox). The combination therapy resulted in greater probing depth reductions.
(Novak M et al. 2008)

65. CONCLUSION
• Plaque bacteria are essential for periodontitis to occur but are insufficient by themselves to
cause the disease. For periodontitis to develop, a susceptible host is also required.
• As we know the majority of periodontal destruction is caused by host immuno-inflammatory
response, various advanced treatment modalities have been introduced in the recent years
including HMT.
• Though various agents are there to modulate host response, only few have shown
successful result in humans. So the further research is needed.

66. References
• Newman M, Takei H, Klokkevold P, Carranza F. “Clinical Periodontology”,10,11th, Edition.
Saunders, Elsevier. Preshaw PM. Host response modulation in periodontics. Periodontol 2000.
2008;48:92-110. Review.
• D W Paquette & R C. Williams. Modulation of host inflammatory mediators as a treatment
strategy for periodontal diseases.
• Minkle Gulati, Vishal Anand, Vivek Govila, and Nikil Jain. Host modulation therapy: An
indispensable part of perioceutics. JIndian Soc Periodontol. 2014 MayJun;18(3): 282–288.

67. • Bartold P, Cantley & Haynes D, Mechanisms and control of pathologic bone loss in periodontitis.
Periodontol 2000, 2010, 55–69
• Preshaw P et al. Subantimicrobial dose doxycycline as adjunctive treatment for periodontitis. A
review. J Clin Periodontol 2004; 31: 697–707
• Serhan C and Chiang N. Endogenous pro-resolving and anti-inflammatory lipid mediators: a new
pharmacologic genus. British Journal of Pharmacology (2008) 153, 200-215

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